RARE DISEASE
Pneumonia caused by Pseudomonas aeruginosa infection
Pneumonia caused by Pseudomonas aeruginosa infection
Pneumonia caused by Pseudomonas aeruginosa infection
Drug discovery
8
drugs
With orphan designations
Overview
Pseudomonas aeruginosa pneumonia is a severe infection primarily associated with healthcare settings, particularly ventilator-associated pneumonia (VAP) in ICU patients. It accounts for ~20% of ICU-acquired pneumonias and carries high mortality (28–42.8%) due to intrinsic antibiotic resistance and frequent multidrug-resistant (MDR) strains. Community-acquired cases are rare (0.9–4.2%) but linked to chronic lung diseases like COPD or bronchiectasis [1][2][4][6][12].
Population
High-risk groups: ICU patients on mechanical ventilation, immunosuppressed individuals (neutropenia, cystic fibrosis), and those with structural lung disease (COPD, bronchiectasis) [1][6][12][16].
Prior P. aeruginosa colonization, recent hospitalization, or antibiotic use increases susceptibility [4][12][19].
Burden
Mortality: 30-day mortality reaches 28% in CAP and 42.8% in VAP; MDR strains increase mortality risk [2][12][17].
Economic impact: Hospital-acquired cases incur €19,000+ additional costs due to prolonged ICU stays [9].
Antibiotic resistance: MDR strains cause 33% of VAP cases globally, with resistance rates exceeding 80% in high-risk regions [12][14].
Therapies
Empirical therapy: Novel β-lactam/β-lactamase inhibitors (ceftolozane-tazobactam, ceftazidime-avibactam) or cefiderocol for suspected MDR strains [3][8][13].
Definitive therapy: Guided by susceptibility testing; avoid unnecessary antipseudomonal drugs in low-risk CAP cases to reduce resistance [2][3][13].
Adjunctive approaches: Investigational therapies (phages, vaccines) for refractory MDR/XDR infections [8][14].
Categories: rare respiratory diseases
Research Papers
924 drug discovery papers about Pneumonia caused by Pseudomonas aeruginosa infection, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
924 drug discovery papers about Pneumonia caused by Pseudomonas aeruginosa infection, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-14 | Real-World Data on the Effectiveness and Use of Intravenous Fosfomycin for the Treatment of Difficult-to-Treat Infections Caused by Carbapenem-Resistant Gram-Negative Bacteria-A Subgroup Analysis from the FORTRESS Study.
This subgroup analysis of the FORTRESS study aimed to evaluate clinical and microbiological outcomes, treatment patterns, and safety of intravenous fosfomycin (FOS)-containing regimens for the treatment of infections due to carbapenem-resistant (CR) Gram-negative bacteria in a real-world setting. Interim data from patients treated with FOS for infections due to CR pathogens were analyzed from the ongoing prospective, multicenter, multinational, observational FORTRESS study. Key outcomes included patient demographics, clinical and infection characteristics at baseline, treatment patterns, and indications of FOS use, as well as clinical, microbiological, and safety outcomes. Exploratory Firth univariate and multivariate logistic regression were performed to identify factors associated with successful clinical response. The subgroup included 161 patients (median age 60 years, 30.4% female, median APACHE II score 15), of whom 59.6% required intensive care, and 41.6% had sepsis at baseline. The most common indications for FOS therapy were hospital-acquired/ventilator-associated pneumonia (28.0%), bacteremia/sepsis (26.1%), and complicated urinary tract infections (24.8%). Infections were predominantly caused by Klebsiella pneumoniae (62.7%), Pseudomonas aeruginosa (28.6%), and Acinetobacter baumannii (17.4%). Carbapenem resistance was mainly mediated by Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-β-lactamase (NDM). In the majority of patients, FOS was part of a combination regimen (91.3%), with ceftazidime-avibactam being the most frequently used partner antibiotic. Overall, clinical success was achieved in 79.4% of patients, while the successful clinical response and microbiological cure rates were 87.5% and 81.3% at the end of FOS treatment, respectively. All-cause in-hospital mortality was 9.9%. Electrolyte imbalances were the most commonly reported adverse drug reactions, but they were mostly not treatment-limiting. The real-world data of this subgroup analysis suggest that FOS-containing regimens were associated with generally favorable clinical and microbiological outcomes and acceptable tolerability in patients with severe infections due to CR Gram-negative bacteria.
2026-08-11 | Mitophagy IncreasesResistance against Infection of Pseudomonas aeruginosa through the PHB2 / PARL / PGAM5 / PINK1 Axis
Abstract Pseudomonas aeruginosa (P.a) is a common opportunistic pathogen causing serious infection and complications in diverse populations, especially under immunodeficient conditions. Previous studies indicate that mitophagy activation is related to multiple conditions and processes in the human body, including infectious diseases. It has been recently implicated that the PARL-PGAM5-PINK1 axis activates mitophagy, but its regulatory role in pneumonia is unclear. We hypothesize that mitophagy receptor PHB2 orchestrates an autophagic process through PARL and PGAM5 to limit P.a. infection and inflammation. By knocking down PHB2, we explored the regulatory role of mitophagy in P.a infection and evaluated the underlying mechanism of the PARL-PGAM5-PINK1 signals both in vitro and in P.a pneumonia mice. Our study also reveals that the critical factors, such as PARL and PINK1, may have potential for therapeutic targeting during Pseudomonas infection.
2026-08-06 | Genomic diversity of Pseudomonas aeruginosa causing bacteremic pneumonia in an intensive care unit, with emergence of an OXA-796-producing NDM-1 ST773 isolate
Pseudomonas aeruginosa bacteremic pneumonia carries exceptionally high mortality, yet there is a paucity of genomic characterization of the strains causing this infection. We performed hybrid sequencing (Illumina and Oxford Nanopore) of 12 non-redundant P. aeruginosa isolates from patients with severe bacteremic pneumonia admitted to the intensive care unit of a tertiary hospital between 2015 and 2023. The 12 isolates were assigned to nine distinct sequence types, suggesting that severe bacteremic pneumonia can arise from diverse P. aeruginosa lineages rather than being dominated by a single specialized or high-risk clone. In the combined dataset of our isolates and publicly available Korean P. aeruginosa genomes, type III secretion system exotoxin genotypes exoU and exoS showed a mutually exclusive and phylogenetically segregated distribution, as previously reported, with both genotypes represented among bacteremic pneumonia isolates. Carbapenemase genes were detected in only one isolate, PA22 (ST773), which harboured bla NDM-1 together with bla OXA-796 and was the only isolate displaying phenotypic carbapenem resistance and multidrug resistance. To assess the clonal relationship between bla NDM-1 -positive PA22 and the carbapenemase-negative ST773 isolate PA20 and to track the evolution of PA22 resistome within a broader epidemiological context, we investigated the population structure of a global ST773 dataset. Core genome MLST-based minimum spanning trees revealed a deep bifurcation within ST773, separating bla NDM-1 -positive and carbapenemase-negative lineages. Korean ST773 isolates formed two distinct clusters within the NDM-1-positive lineage, with the PA22-containing cluster phylogenetically proximal to isolates from the United States. Within the NDM-1-positive Korean cluster, bla OXA-796 was located in conserved class 1 integron gene cassette arrays that exhibit ongoing structural diversification among closely related isolates, evidenced by variable integration of IS110 elements. Our findings demonstrate that severe bacteremic pneumonia arises from phylogenetically diverse P. aeruginosa lineages and provide genomic context for the NDM-1-producing ST773 clone that is rapidly emerging in Korea.
2026-07-22 | Multifaceted effects of galU deletion on phenotype and virulence of Pseudomonas aeruginosa in vitro and in vivo
Pseudomonas aeruginosa is a widespread Gram-negative opportunistic pathogen in environmental and hospital settings, frequently causing respiratory diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disorder (COPD) and ventilator-associated pneumonia. In our previous study, a galU-deleted clinical P. aeruginosa was found to exhibit increased susceptibility to polymyxins. The galU gene plays an important role in the biosynthesis of lipopolysaccharide (LPS) O-antigen. Here, we systematically evaluated the effects of galU deletion on the phenotype and virulence of P. aeruginosa PAO1. A galU deletion mutant was successfully constructed in P. aeruginosa PAO1 by CRISPR/Cas9, and the complementation was accomplished by pUCP18 plasmid carrying wildtype galU. The changes in phenotype, virulence and pathogenicity were systemically studied. The results revealed that knockout of galU led to the loss of O-antigen, which affected growth, virulence and pathogenicity through various ways in P. aeruginosa, and significantly affected the susceptibility of P. aeruginosa to polymyxins. Mechanism study suggested the involvements of quorum sensing, Entner-Doudoroff pathway and tyrosine metabolism, etc on bacterial virulence, antibiotic susceptibility changes after galU deletion. galU and the related pathways may serve as effective targets for treatment of P. aeruginosa infection, providing a theoretical basis for the development of novel antibacterial drugs.
2026-06-25 | Salvage Treatment of Ventilator-Associated Pneumonia Using Sulbactam-Durlobactam in a Preterm Neonate: A Case Report.
Ventilator-associated pneumonia (VAP) is a leading cause of nosocomial infections in neonatal intensive care units (NICUs) and is associated with significant morbidity, mortality, and prolonged hospitalization, particularly in preterm neonates. Management is complicated by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens, with very limited evidence supporting the use of reserve antibiotics in this population. We report a male neonate born at 25 weeks of gestation (birth weight 740 g) who developed severe VAP caused by XDR Acinetobacter calcoaceticus-baumannii complex and Pseudomonas aeruginosa. After failure of multiple antibiotic regimens, including ampicillin, amikacin, meropenem, vancomycin, cefepime with inhaled colistin, tigecycline, and ceftazidime-avibactam combined with fosfomycin, the infant was treated with sulbactam-durlobactam (25 mg/kg/dose every 6 h) in combination with ceftazidime-avibactam. After 12 days of this regimen, the neonate was successfully extubated. This case highlights the therapeutic challenges of XDR infections in extremely preterm neonates and suggests that sulbactam-durlobactam may represent a viable salvage treatment option. Further pharmacokinetic and clinical studies are needed to establish optimal dosing and safety in the neonatal population.
proteins
2026-04-23 | Marine antimicrobial peptide scyreprocin exhibits therapeutic potential against multidrug-resistant bacteria in wound and lung infections with low resistance.
Antibiotic resistance, driven by multidrug-resistant (MDR) pathogens, poses a major global health threat. Antimicrobial peptides (AMPs) have garnered significant attention as promising therapeutic agents for combating MDR bacteria. Here, we demonstrate the potent antimicrobial activity of scyreprocin against MDR strains, including Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Notably, scyreprocin eradicated the tested strains without inducing drug resistance, inhibited biofilm formation, and eliminated persister cells. In terms of in vivo efficacy, scyreprocin displayed excellent activity against S. aureus and K. pneumoniae in a full-thickness wound infection model. Furthermore, administration of scyreprocin reduced bacterial burden in a K. pneumoniae lung infection model, thereby attenuating the pulmonary inflammatory response. Crucially, under cumulative administration of 25 mg/kg for 5 days, scyreprocin treatment via intravenous injection exerted no in vivo toxicity to mice. Mechanistic studies indicated that scyreprocin triggered membrane damage by causing rapid membrane permeability and leakage. Taken together, the marine-sourced scyreprocin demonstrates effective therapeutic potential for treating infections caused by drug-resistant pathogens.
2026-03-25 | Antimicrobial Peptides and ESKAPEE Pathogens: A New Frontier in the Fight Against Antimicrobial Resistance.
Antimicrobial resistance is the most critical global health challenge, largely complicating the treatment of infections caused by multi-drug-resistant pathogens. Among them, ESKAPEE pathogens comprise Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli, which emerged as significant pathogens due to their ability to evade conventional antibiotics. These pathogens cause millions of infections and thousands of deaths every year, mainly in the healthcare sector. Their resistance mechanisms may include modification of targets for antibiotics, increased efflux pump activity, decreased influx, and inactivation of antibiotics. Antimicrobial peptides (AMPs) represent a new candidate whose broad-spectrum activity against microorganisms often protects against susceptible pathogens. AMPs, naturally present in most living organisms as part of innate immunity, are now synthetically produced to harness their antimicrobial properties in therapeutic applications. Moreover, their mechanisms of action make them unique and capable of circumventing the classical resistance pathways. Thus, they offer hope in combating ESKAPEE pathogens. This review discusses the prevalence and clinical significance of ESKAPEE pathogens, their resistance mechanisms, and the possible roles of AMPs in developing effective therapy. With these escalating trends in AMR globally, understanding their dynamics is of prime importance to improve infection control measures and patient outcomes in critical care environments. In addition to an overview of available information on the biology and drug-resistance mechanisms of these pathogens, the review also evaluates the antimicrobial activity of AMPs against multidrug-resistant bacteria, discusses their benefits compared to traditional antibiotics, and highlights significant drawbacks that could limit their clinical use.
2026-02-26 | Pharmacodynamic evaluation of BRII-693, a next-generation synthetic macrocyclic peptide antibiotic, in the neutropenic mouse thigh and lung infection models against gram-negative pathogens.
BRII-693 is a next-generation synthetic macrocyclic peptide antibiotic for infections caused by drug-resistant gram-negative pathogens. This study evaluated the pharmacodynamic activity of BRII-693 against common gram-negative pathogens using neutropenic mouse thigh (11 strains) and lung (15 strains) infection models. BRII-693 exhibited dose-dependent increases in pharmacokinetic exposure in both plasma and epithelial lining fluid (ELF). Due to its prolonged elimination half-life within ELF, the ELF area under the curve (AUC) was higher than plasma AUC on a mg/kg basis. In dose-ranging PK/PD studies, BRII-693 demonstrated dose-dependent antibacterial activity. In both the thigh and lung models, bacterial stasis was achieved at 24 h plasma AUC/MIC values of 1-19 for Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, and 1-log kill required only modestly higher targets given the steep exposure-response relationships. Higher target exposures were noted for Pseudomonas aeruginosa studies. In the lung model, BRII-693 achieved robust cidal endpoints against all tested organisms. Maximal effect (3-4 log reduction in bacterial burden) converged at a 24 h plasma AUC/MIC value of 50. These findings demonstrate robust PK/PD profile and in vivo efficacy of BRII-693 against clinically relevant gram-negative pathogens, supporting its potential as a next-generation macrocyclic peptide antibiotic.
2026-02-24 | Myeloid-derived interleukin-10 induced by thrombospondin-1 mediates host defense and regulates inflammation during acute bacterial lung infection
ABSTRACT Pseudomonas aeruginosa ( P. aeruginosa ) is a leading cause of hospital- and ventilator-associated pneumonia, driven by virulence factors that damage lung tissue. Neutrophils and monocytes are myeloid immune cells that play key roles in host defense during pulmonary infection against P. aeruginosa ; although if not properly regulated, their inflammatory activity can lead to severe lung injury. Thrombospondin-1 (TSP-1) is a host glycoprotein that regulates neutrophil activation in the lungs during P. aeruginosa infection, protecting the host from mortality. Here, we demonstrate that in addition to regulating the pro-inflammatory phenotype of neutrophils, during P. aeruginosa infection, TSP-1 induces IL-10 in the lung tissue of mice inoculated with this bacterium. Our data show that neutrophils and Ly6C + monocytes are major sources of lung IL-10 during the first 48 h post-infection, a cytokine that is required for host survival, host defense, and to reduce lung inflammation and injury. Further in vitro studies determined that TSP-1 induces IL-10 production in lipopolysaccharide-stimulated CD11b + Ly6G + Ly6C + cells differentiated from bone marrow precursors through a mechanism dependent on the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Importantly, intratracheal transfer of IL-10 +/+ CD11b + Ly6G + Ly6C + cells 1 day before infection to Thbs1 −/− mice restored their ability to produce IL-10 in the lungs, improved host defense, and reduced lung inflammation and permeability upon infection. Altogether, our data show that TSP-1 induces IL-10 production in neutrophils and monocytes, enhancing host defense while reducing lung inflammation.
2025-11-18 | Engineered Mycoplasma pneumoniae targeting dual-species bacterial biofilms: a novel strategy against infections.
Antimicrobial resistance is a major global health threat, potentially causing 8.22 million deaths annually by 2050. Polymicrobial biofilms significantly contribute to this crisis, leading to treatment failure, especially in chronic airway infections caused by Staphylococcus aureus and Pseudomonas aeruginosa, common in ventilator-associated pneumonia and cystic fibrosis. To address this, we engineered an attenuated Mycoplasma pneumoniae strain, CV8_HAD, to secrete biofilm-disrupting enzymes (PelAh, PslGh, A1-II' and Dispersin B). CV8_HAD showed strong in vitro activity against single and mixed-species biofilms of S. aureus and P. aeruginosa, and demonstrated in vivo efficacy against S. aureus biofilms in mice and mixed infections in Galleria mellonella larvae. This study establishes engineered M. pneumoniae as a promising therapeutic strategy for tackling microbial biofilms and highlights the potential of G. mellonella larvae models as an alternative to mouse models in advancing research on biofilm-targeting interventions.
vaccines
2025-07-25 | Development of a bivalent protein subunit vaccine against infection by Pseudomonas aeruginosa and Staphylococcus aureus
Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA) are members of the ESKAPE pathogens, a group of bacteria that are a threat to human health due to their ability to resist antibiotics. They are known to cause severe infections, often as co-morbidities, in individuals with conditions such as people with cystic fibrosis, diabetes, wounds, pneumonia, and critically ill patients requiring intubation leading to ventilator-associated pneumonia. Emergence of multi-drug resistance in SA and PA is making traditional antibiotic treatment ineffective and unfortunately there are no licensed vaccines to prevent MRSA or PA infections. We have demonstrated that when delivered intranasally (IN) L-PaF, a genetic fusion of the PA type III secretion system (T3SS) proteins PcrV and PopB (PaF) with LTA1, the active moiety of heat-labile enterotoxin from enterotoxigenic E. coli, protects against PA. L-PaF was formulated as a nanoemulsion (ME) to increase the protective immune response against clinically relevant PA strains in a mouse lung colonization model. With the addition NEAT2, the heme capturing domain of the SA protein IsdB, a bivalent vaccine was generated. IN administration of the bivalent formulation protected MRSA pre-exposed mice from both MRSA and PA infection. Sera from mice vaccinated with our formulation contained strong IgG titers with high levels of opsonophagocytic killing of homologous and heterologous PA and SA strains. Additionally, the bivalent L-PaF/NEAT2 formulation elicited stimulation of IL-17A and IL-2 cytokines. Because established PA and SA lung infection models with rabbits better reproduce the clinical hallmarks of severe human acute pneumonia, rabbits were immunized with the bivalent L-PaF/NEAT2 formulation. All of the vaccinated rabbits survived the challenges while the controls did not. These findings demonstrate that our L-PaF/ME/NEAT2 formulation has potential as a broad-spectrum vaccine against both SA and PA infection.
2025-07-06 | In silico development of a broad-spectrum vaccine against ESKAPE pathogens.
Antimicrobial-resistant ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae) have significantly restricted therapeutic alternatives for critical infections, consequently contributing to increase the severity and mortality of infectious illnesses that represent a significant global health challenge. Vaccination as a preventive measure can be crucial in substantially reducing bacterial infections and is potentially effective against antibiotic-resistant bacteria. This study shows the design of an epitope-based vaccine capable of neutralizing shared antigenic determinants present among the ESKAPE pathogens. The pangenome of the ESKAPE pathogens was analyzed to extract the core proteome. This approach facilitated reverse vaccinology analysis to identify antigenic proteins within this bacterial group. The study revealed similar structures in porins OmpA, OprD, and TolC, as well as the collagen-binding adhesins Acm and Cna. These proteins were then utilized to predict T-cell and B-cell epitopes, selecting those with their best physicochemical properties, antigenicity, non-allergenicity, and lack of toxicity. Additionally, epitopes located on the surface of the antigens and capable of coupling with HLA molecules were prioritized. In this computational approach, we engineered a construct incorporating the adjuvant RS09, a TLR4 agonist, and immunogenic epitopes connected by linkers. We assessed the stability of their interaction with pattern recognition receptors of the immune system through molecular docking and molecular dynamics simulations. The in silico immune simulation demonstrated that the vaccine could trigger humoral and cell-mediated immune responses. The resulting construct potentially represents an effective and safe vaccine candidate to prevent infections caused by the ESKAPE group.
2024-12-25 | Hybrid Cell Membrane-Engineered Nanocarrier for Triple-Action Strategy to Address Pseudomonas aeruginosa Infection.
Bacterial infections resistant to antimicrobial treatments, particularly those caused by Pseudomonas aeruginosa (P. aeruginosa), frequently lead to elevated mortality rates. Tackling this resistance using therapeutic combinations with varied mechanisms has shown considerable promise. In this study, a bioinspired nanocarrier is successfully designed and engineered for targeted antibiotic delivery and toxin/bacteria clearance. This is achieved by encapsulating antibiotic-loaded framework nucleic acids with hybrid cell membranes acquired from neutrophils and platelets. By coating the hybrid membrane outside the shell, nanocarriers are endowed with the function of neutrophil-like chemotaxis and platelet-like bacteria adhesion to achieve the first stage of inflammation targeting. Based on the specific binding of bacteria toxin to the hybrid membrane, the release of antibiotic-loaded framework nucleic acids is triggered by toxin-mediated membrane lysis to fulfill the second stage of toxin neutralization and bacteria killing. Meanwhile, the immunomodulation potential of framework nucleic acids enables nanocarriers to accomplish the third stage of reversing the immunosuppressive microenvironment. In mouse models of acute and chronic P. aeruginosa pneumonia, the nanocarriers can reduce bacterial burden at a low dosage and decrease mortality with negligible toxicity. In sum, these findings have illustrated the remarkable capability of nanocarriers in treating recalcitrant bacterial infections.
2024-11-18 | Mucosal immunization with the lung Lactobacillus-derived amphiphilic exopolysaccharide adjuvanted recombinant vaccine improved protection against P. aeruginosa infection.
Respiratory infections caused by Pseudomonas aeruginosa are a major health problem globally. Current treatment for P. aeruginosa infections relies solely on antibiotics, but the rise of antibiotic-resistant strains necessitates an urgent need for a protective vaccine. Traditional parenteral vaccines, despite employing potent adjuvants aimed at serotype-dependent immunity, often fail to elicit the desired mucosal immune response. Thus, developing vaccines that target both localized mucosal and systemic immune responses represents a promising direction for future research on P. aeruginosa vaccination. In this study, we explored EPS301, the exopolysaccharide derived from the lung microbiota strain Lactobacillus plantarum WXD301, which exhibits excellent self-assembly properties, enabling the formation of homogeneous nanoparticles when encapsulating recombinant PcrV of P. aeruginosa, designated as EPS301@rPcrV. Notably, the EPS301 vector effectively enhanced antigen adhesion to the nasal and pulmonary mucosal tissues and prolonged antigen retention. Moreover, EPS301@rPcrV provided effective and sustained protection against P. aeruginosa pneumonia, surpassing the durability achieved with the "gold standard" cholera toxin adjuvant. The EPS301-adjuvanted vaccine formulation elicited robust mucosal IgA and Th17/γδ17 T cell responses, which exceeded those induced by the CTB-adjuvanted vaccination and were sustained for over 112 days. Additionally, Th 17 and γδ 17 resident memory T cells induced by EPS301@rPcrV were crucial for protection against P. aeruginosa challenge. Intriguingly, IL-17A knockout mice exhibited lower survival rates, impaired bacterial clearance ability, and exacerbated lung tissue damage upon EPS301 adjuvanted vaccination against P. aeruginosa-induced pneumonia, indicating an IL-17A-dependent protective mechanism. In conclusion, our findings provided direct evidence that EPS301@rPcrV mucosal vaccine is a promising candidate for future clinical application against P. aeruginosa-induced pulmonary infection.
2023-11-01 | A protein-free vaccine stimulates innate immunity and protects against nosocomial pathogens.
Traditional vaccines are difficult to deploy against the diverse antimicrobial-resistant, nosocomial pathogens that cause health care-associated infections. We developed a protein-free vaccine composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan that improved survival and reduced bacterial burden of mice with invasive blood or lung infections caused by methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, extended-spectrum beta-lactamase-expressing Escherichia coli, and carbapenem-resistant strains of Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The vaccine also conferred protection against the fungi Rhizopus delemar and Candida albicans. Efficacy was apparent by 24 hours and lasted for up to 28 days after a single vaccine dose, with a second dose restoring efficacy. The vaccine acted through stimulation of the innate, rather than the adaptive, immune system, as demonstrated by efficacy in the absence of lymphocytes that were abrogated by macrophage depletion. A role for macrophages was further supported by the finding that vaccination induced macrophage epigenetic alterations that modulated phagocytosis and the inflammatory response to infection. Together, these data show that this protein-free vaccine is a promising strategy to prevent deadly antimicrobial-resistant health care-associated infections.
gene therapies
2026-06-27 | Inhalable bacteriophage endolysins: a novel therapeutic strategy for drug-resistant bacterial pulmonary infections - a comprehensive review.
Pulmonary infections caused by multidrug-resistant (MDR) bacteria pose a severe global health threat with high mortality rates, especially in hospital-acquired pneumonia. The stagnation of new antibiotic development underscores the urgent need for alternative therapeutics. This review summarizes recent advances in the application of bacteriophage endolysins against major MDR respiratory pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. We focus on their mechanisms of action, synergistic effects with antibiotics, and efficacy against biofilms. Endolysins demonstrate potent and species-specific lytic activity against a broad spectrum of MDR bacteria. A key advantage is their low propensity for inducing resistance. Critically, when administered via optimized inhalation delivery systems, endolysins can achieve high local concentrations in the lungs - though this depends on factors such as the aerosol device, formulation properties and patient-related variables - effectively eradicating pathogens in animal models of pneumonia with minimal systemic toxicity. This direct pulmonary delivery approach bypasses many challenges associated with systemic administration and enhances therapeutic outcomes. Endolysins represent a promising paradigm shift in combating drug-resistant bacterial pulmonary infections. Their rapid lytic activity, synergy with conventional antibiotics, and suitability for inhalable formulation position them as a potent adjunct or alternative therapy. While challenges in stabilization and large-scale production remain, advancing inhalation delivery systems for endolysins holds immense potential to holds immense potential to revolutionize the treatment of recalcitrant respiratory infections.
2026-03-27 | Mapping the clinical use of inhaled bacteriophages in respiratory infections caused by multidrug-resistant pathogens: a scoping review.
Inhaled bacteriophage therapy is an emerging adjunctive strategy for treating lower respiratory tract infections caused by multidrug-resistant (MDR) pathogens. However, the clinical evidence base remains fragmented. We conducted a scoping review to map the current landscape of human studies using nebulized, aerosolized, or dry-powder phage therapy for pulmonary infections. We systematically searched PubMed, Scopus, Web of Science, and ClinicalTrials.gov for clinical studies published up to 1 June 2025. Eligible studies included clinical trials, cohort studies, and case reports/series reporting at least one dose of inhaled lytic phage for bacterial respiratory infections. Screening followed PRISMA-ScR guidelines. Key data were extracted on patient characteristics, pathogens, phage preparations, delivery methods, safety, and outcomes. Of 507 records identified, 31 studies met inclusion criteria: six clinical trials and 25 case reports or series. Target infections included ventilator-associated pneumonia, cystic fibrosis exacerbations, and chronic bronchiectasis, primarily due to Pseudomonas aeruginosa, Acinetobacter baumannii, or Klebsiella pneumoniae. Delivery methods varied widely, including nebulizers, dry-powder inhalers, and endotracheal instillation. Most studies reported clinical or microbiological improvement without major adverse events, though few used standardized outcome measures. Inhaled phage therapy has shown promise in compassionate and investigational settings for MDR respiratory infections. Despite heterogeneity in delivery methods and outcome reporting, preliminary data suggests feasibility and safety. Standardized protocols and controlled trials are needed to define its role in pulmonary antimicrobial therapy.
2026-02-22 | <b>Evaluating a Novel Bacteriophage Cocktail for Eradicating Pseudomonas aeruginosa Biofilms in Ventilator-Associated Pneumonia</b>
Background: Ventilator-associated pneumonia caused by Pseudomonas aeruginosa remains difficult to treat because of multidrug resistance and biofilm formation, which reduce antibiotic penetration and contribute to persistent infection in mechanically ventilated patients. Objective: To evaluate the efficacy of adjunctive nebulized bacteriophage cocktail therapy in reducing P. aeruginosa biofilm burden and improving microbiological and clinical outcomes in ventilator-associated pneumonia. Methods: A parallel-group randomized controlled trial was conducted in tertiary care intensive care units over five months. Seventy-two mechanically ventilated adults with microbiologically confirmed P. aeruginosa ventilator-associated pneumonia and evidence of biofilm formation were randomized to receive either standard culture-guided antibiotic therapy plus nebulized bacteriophage cocktail twice daily for 14 days or standard care alone. Primary outcomes were biofilm biomass reduction and microbiological clearance; secondary outcomes included duration of mechanical ventilation, Clinical Pulmonary Infection Score, and intensive care unit stay. Results: The final analyzed cohort included 63 participants. Day-14 biofilm biomass was significantly lower in the intervention group than in controls (0.62 ± 0.18 vs 0.94 ± 0.22 OD units; p<0.001). Culture negativity was higher with bacteriophage therapy (75.0% vs 45.2%; p=0.01). The intervention group also had shorter mechanical ventilation duration, lower day-14 Clinical Pulmonary Infection Score, and reduced intensive care unit stay (p<0.05 for all). Conclusion: Adjunctive nebulized bacteriophage cocktail therapy improved biofilm reduction, microbiological clearance, and short-term clinical outcomes in P. aeruginosa ventilator-associated pneumonia.
2025-12-16 | Navigating the Crisis of Multidrug-Resistant Infections in Infants to Teenagers: Regional Variability and Global Solutions
Superbacteria, or multidrug-resistant (MDR) microorganisms, pose a major global health threat, particularly in regions such as South Asia and sub-Saharan Africa. Bacteria, such as Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa, are resistant to multiple antibiotics, making infections more difficult to treat. These resistant infections cause millions of deaths annually, with vulnerable groups, such as neonates and children, being particularly at risk. The overuse of antibiotics in medicine and livestock, along with weak healthcare systems, accelerates the spread of antibiotic resistance, especially in countries such as India, China, and Pakistan. Common resistant infections include urinary tract infections, neonatal sepsis, and ventilator-associated pneumonia (VAP). Resistance to antibiotics, such as carbapenems and third-generation cephalosporins, along with the rise of ESBL-producing bacteria, complicates treatment, particularly in neonatal intensive care units (NICUs). This paper reviews global data on superbacteria, focusing on neonatal and pediatric populations, highlighting the need for better diagnostics, novel treatments (e.g., phage therapy), antimicrobial stewardship, infection control, and global cooperation to combat the growing threat of resistance.
2025-11-13 | Efficacy of Phage Cocktails Against Biofilms Formed by Antibiotic-Resistant Bacteria.
The rapid spread of multidrug-resistant strains of Klebsiella pneumoniae and Pseudomonas aeruginosa, along with their ability to form biofilms on various medical devices, significantly complicate the treatment of infections caused by these microorganisms and render antibiotic therapy ineffective. In contrast, the use of bacteriophages is a promising alternative for combating antibiotic-resistant biofilm-forming strains of K.pneumoniae and P.aeruginosa. Two cocktails of 14 bacteriophages (nine Klebsiella phages and five Pseudomonas phages) were used to control biofilms formed by XDR (Extensively Drug-Resistant) strains of K. pneumoniae and P. aeruginosa under in vitro conditions. The K. pneumoniae strain harbored genes associated with biofilm formation fimH, mrkA, matBecp and antibiotic resistance blaNDM-1, blaKPC, blaOXA-48, blaCTX-M-1, blaTEM . The P. aeruginosa strain carried genes associated with biofilm formation algD, PslD, PelF and antibiotic resistance blaNDM-1 .Bacteriophages were isolated from the wastewater samples. Biofilms were formed on various substrates (glass slides, wells of polystyrene plates, and polyvinyl chloride vascular catheters) and analyzed using optical and scanning electron microscopy, as well as gentian violet staining assays. The results demonstrated that bacteriophage cocktails could effectively degrade biofilms of K. pneumoniae and P. aeruginosa. Biofilms formed on catheter segments, polystyrene plate wells, and glass slides were treated with lytic bacteriophages at concentrations of at least 10^7 PFU/mL. After 24 h of treatment with phage cocktails, a 34.5% reduction in biofilm biomass was observed on the catheters for K. pneumoniae strain No. 361 and 34.1% for P. aeruginosa strain No. 7. In polystyrene plate wells, the reductions were 39.3% and 52.8%, respectively. The experimental results indicate the effectiveness of phage cocktails in reducing biofilm biomass and bacterial viability. Given the ability of phages to degrade biofilms, phage therapy may become a promising adjunct to standard treatment methods for infections caused by multidrug-resistant pathogens.
other
2026-06-17 | Engineering low-endotoxin lipid A in a double auxotroph Pseudomonas aeruginosa to develop safer whole-cell vaccines.
Pseudomonas aeruginosa is a highly adaptable Gram-negative bacterium causing severe respiratory infections, particularly in vulnerable populations. The rise of antimicrobial resistance highlights the urgent need for effective vaccines. We previously developed a live-attenuated vaccine candidate, PAO1 ΔmurI Δalr ΔdadX, a genetically stable double auxotrophic strain that exhibited dose-dependent reactogenicity upon intranasal administration in mice, likely due to lipid A component of lipopolysaccharide (LPS). To reduce LPS-associated toxicity while preserving immunogenicity, we engineered novel strains by inactivating genes involved in lipid A biosynthesis (htrB1, htrB2) or modification (pagP, pagL). Lipid A structural modifications were confirmed by MALDI-TOF MS. Mutants were evaluated for Toll-like receptor 4 (TLR4) activation, virulence attenuation, and their ability to induce immune responses and protection in an acute pneumonia model. All engineered strains displayed modified lipid A structures. Mutations in htrB1 and htrB2 reduced TLR4 activation and significantly attenuated virulence following intraperitoneal challenge in mice. Inactivation of pagL resulted in minimal attenuation, whereas pagP inactivation led to marked attenuation without altering TLR4 activation. In the acute pneumonia model, all mutants elicited robust systemic and mucosal immune responses, and conferred strong protection, despite transient weight loss following intranasal administration. Targeted lipid A modification represents an effective strategy to reduce in vitro reactogenicity while preserving immunogenicity in live-attenuated P. aeruginosa vaccine candidates. Although further optimization may minimize residual in vivo effects, these findings support the potential of engineered strains as vaccine candidates for preventing respiratory infections caused by P. aeruginosa.
2026-06-17 | Engineered antibodies bypass bacterial immune evasion to drive complement-mediated protection against lethal infections.
The expanding global crisis of bacterial infections caused by antimicrobial-resistant pathogens has resulted in an urgent need for therapeutics. Previous efforts to target pathogen surface antigens with monoclonal antibodies (mAbs) have sought to activate the complement system, primarily through the antibody-dependent classical pathway. However, most mAbs have induced insufficient complement activation because pathogen evasion strategies disrupt the complex spatiotemporal requirements for activation of the classical pathway initiation complex C1. To address this, we developed a targeted complement activation therapy (T-CAT), which uses antibodies furnished with the enzymatic capability to initiate complement activation directly on the bacterial surface without involvement of the classical pathway initiation complex. We found that T-CAT mAbs directed against bacterial surface antigens can overcome the strategies that pathogens evolved to escape from classical pathway-mediated clearance by the immune system. We further demonstrated that T-CAT mAbs could safely and effectively be used to treat infectious disease in experimental murine models of sepsis and pneumonia caused by Klebsiella pneumoniae, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Neisseria meningitidis. Together, these data highlight the potential for T-CAT as a next-generation mAb platform with broad applicability against diverse microbial species, including multidrug-resistant pathogens, without promoting drug resistance.
2026-06-12 | AZinc-Coordinated Glycopolymer for Inhibiting BacterialToxins in Management of Acute Pneumonia
Bacterial toxins play a critical role in infections by compromising host defenses, causing host cell death, and inducing excessive immune activation, ultimately leading to severe tissue damage and increased mortality. To combat both the pathogen and its associated toxins, this study developed a bacteria-targeting zinc-coordinated glycopolymer designed to deliver antisense oligonucleotides (ASOs) and absorb lipopolysaccharides (LPS). The functional polymer enhances Pseudomonas aeruginosa internalization efficiency through galactose-mediated bacterial surface interaction. By delivering multiple ASOs, the nanoparticle enables the dual suppression of bacterial growth and quorum sensing, exhibiting potent antibacterial activity. Furthermore, zinc ions coordinated within the glycopolymer impart the ability to bind and adsorb LPS, thereby mitigating the toxin-induced damage to host cells. In a murine model of acute pneumonia, this approach significantly improved survival rates and reduced pro-inflammatory cytokine levels. Consequently, pulmonary inflammation was suppressed, bacterial toxin-induced damage was alleviated, and tissue integrity was preserved. This synergistic strategy of combined sterilization and toxin neutralization offers a novel and synergistic therapeutic approach to combating bacterial infections.
2026-06-01 | Data Sheet 1_Engineering low-endotoxin lipid A in a double auxotroph Pseudomonas aeruginosa to develop safer whole-cell vaccines.pdf
Introduction Pseudomonas aeruginosa is a highly adaptable Gram-negative bacterium causing severe respiratory infections, particularly in vulnerable populations. The rise of antimicrobial resistance highlights the urgent need for effective vaccines. We previously developed a live-attenuated vaccine candidate, PAO1 ΔmurI Δalr ΔdadX, a genetically stable double auxotrophic strain that exhibited dose-dependent reactogenicity upon intranasal administration in mice, likely due to lipid A component of lipopolysaccharide (LPS). Methods To reduce LPS-associated toxicity while preserving immunogenicity, we engineered novel strains by inactivating genes involved in lipid A biosynthesis (htrB1, htrB2) or modification (pagP, pagL). Lipid A structural modifications were confirmed by MALDI-TOF MS. Mutants were evaluated for Toll-like receptor 4 (TLR4) activation, virulence attenuation, and their ability to induce immune responses and protection in an acute pneumonia model. Results All engineered strains displayed modified lipid A structures. Mutations in htrB1 and htrB2 reduced TLR4 activation and significantly attenuated virulence following intraperitoneal challenge in mice. Inactivation of pagL resulted in minimal attenuation, whereas pagP inactivation led to marked attenuation without altering TLR4 activation. In the acute pneumonia model, all mutants elicited robust systemic and mucosal immune responses, and conferred strong protection, despite transient weight loss following intranasal administration. Discussion Targeted lipid A modification represents an effective strategy to reduce in vitro reactogenicity while preserving immunogenicity in live-attenuated P. aeruginosa vaccine candidates. Although further optimization may minimize residual in vivo effects, these findings support the potential of engineered strains as vaccine candidates for preventing respiratory infections caused by P. aeruginosa.
2026-05-13 | Current prospects in the development of vaccines against pseudomonas aeruginosa
Pseudomonas aeruginosa is an opportunistic pathogen with a multidrug-resistant profile that has become a critical threat to global public health. It is one of the leading causes of severe healthcare-associated infections, including ventilator-associated pneumonia, chronic infections in patients with cystic fibrosis, and bloodstream infections in immunosuppressed individuals. The development of vaccines against P. aeruginosa represents a major challenge due to the high capacity of this bacterium to form biofilms, its broad arsenal of virulence factors, and its ability to evade the host immune system. Producing a successful vaccine against P. aeruginosa may be possible in the near future through the use of multivalent strategies, including advanced technologies such as nanotechnology and RNA-based platforms, and by acquiring more detailed knowledge regarding host-pathogen interactions.
small molecules
2026-08-14 | Real-World Data on the Effectiveness and Use of Intravenous Fosfomycin for the Treatment of Difficult-to-Treat Infections Caused by Carbapenem-Resistant Gram-Negative Bacteria-A Subgroup Analysis from the FORTRESS Study.
This subgroup analysis of the FORTRESS study aimed to evaluate clinical and microbiological outcomes, treatment patterns, and safety of intravenous fosfomycin (FOS)-containing regimens for the treatment of infections due to carbapenem-resistant (CR) Gram-negative bacteria in a real-world setting. Interim data from patients treated with FOS for infections due to CR pathogens were analyzed from the ongoing prospective, multicenter, multinational, observational FORTRESS study. Key outcomes included patient demographics, clinical and infection characteristics at baseline, treatment patterns, and indications of FOS use, as well as clinical, microbiological, and safety outcomes. Exploratory Firth univariate and multivariate logistic regression were performed to identify factors associated with successful clinical response. The subgroup included 161 patients (median age 60 years, 30.4% female, median APACHE II score 15), of whom 59.6% required intensive care, and 41.6% had sepsis at baseline. The most common indications for FOS therapy were hospital-acquired/ventilator-associated pneumonia (28.0%), bacteremia/sepsis (26.1%), and complicated urinary tract infections (24.8%). Infections were predominantly caused by Klebsiella pneumoniae (62.7%), Pseudomonas aeruginosa (28.6%), and Acinetobacter baumannii (17.4%). Carbapenem resistance was mainly mediated by Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-β-lactamase (NDM). In the majority of patients, FOS was part of a combination regimen (91.3%), with ceftazidime-avibactam being the most frequently used partner antibiotic. Overall, clinical success was achieved in 79.4% of patients, while the successful clinical response and microbiological cure rates were 87.5% and 81.3% at the end of FOS treatment, respectively. All-cause in-hospital mortality was 9.9%. Electrolyte imbalances were the most commonly reported adverse drug reactions, but they were mostly not treatment-limiting. The real-world data of this subgroup analysis suggest that FOS-containing regimens were associated with generally favorable clinical and microbiological outcomes and acceptable tolerability in patients with severe infections due to CR Gram-negative bacteria.
2026-08-11 | Mitophagy IncreasesResistance against Infection of Pseudomonas aeruginosa through the PHB2 / PARL / PGAM5 / PINK1 Axis
Abstract Pseudomonas aeruginosa (P.a) is a common opportunistic pathogen causing serious infection and complications in diverse populations, especially under immunodeficient conditions. Previous studies indicate that mitophagy activation is related to multiple conditions and processes in the human body, including infectious diseases. It has been recently implicated that the PARL-PGAM5-PINK1 axis activates mitophagy, but its regulatory role in pneumonia is unclear. We hypothesize that mitophagy receptor PHB2 orchestrates an autophagic process through PARL and PGAM5 to limit P.a. infection and inflammation. By knocking down PHB2, we explored the regulatory role of mitophagy in P.a infection and evaluated the underlying mechanism of the PARL-PGAM5-PINK1 signals both in vitro and in P.a pneumonia mice. Our study also reveals that the critical factors, such as PARL and PINK1, may have potential for therapeutic targeting during Pseudomonas infection.
2026-08-06 | Genomic diversity of Pseudomonas aeruginosa causing bacteremic pneumonia in an intensive care unit, with emergence of an OXA-796-producing NDM-1 ST773 isolate
Pseudomonas aeruginosa bacteremic pneumonia carries exceptionally high mortality, yet there is a paucity of genomic characterization of the strains causing this infection. We performed hybrid sequencing (Illumina and Oxford Nanopore) of 12 non-redundant P. aeruginosa isolates from patients with severe bacteremic pneumonia admitted to the intensive care unit of a tertiary hospital between 2015 and 2023. The 12 isolates were assigned to nine distinct sequence types, suggesting that severe bacteremic pneumonia can arise from diverse P. aeruginosa lineages rather than being dominated by a single specialized or high-risk clone. In the combined dataset of our isolates and publicly available Korean P. aeruginosa genomes, type III secretion system exotoxin genotypes exoU and exoS showed a mutually exclusive and phylogenetically segregated distribution, as previously reported, with both genotypes represented among bacteremic pneumonia isolates. Carbapenemase genes were detected in only one isolate, PA22 (ST773), which harboured bla NDM-1 together with bla OXA-796 and was the only isolate displaying phenotypic carbapenem resistance and multidrug resistance. To assess the clonal relationship between bla NDM-1 -positive PA22 and the carbapenemase-negative ST773 isolate PA20 and to track the evolution of PA22 resistome within a broader epidemiological context, we investigated the population structure of a global ST773 dataset. Core genome MLST-based minimum spanning trees revealed a deep bifurcation within ST773, separating bla NDM-1 -positive and carbapenemase-negative lineages. Korean ST773 isolates formed two distinct clusters within the NDM-1-positive lineage, with the PA22-containing cluster phylogenetically proximal to isolates from the United States. Within the NDM-1-positive Korean cluster, bla OXA-796 was located in conserved class 1 integron gene cassette arrays that exhibit ongoing structural diversification among closely related isolates, evidenced by variable integration of IS110 elements. Our findings demonstrate that severe bacteremic pneumonia arises from phylogenetically diverse P. aeruginosa lineages and provide genomic context for the NDM-1-producing ST773 clone that is rapidly emerging in Korea.
2026-07-22 | Multifaceted effects of galU deletion on phenotype and virulence of Pseudomonas aeruginosa in vitro and in vivo
Pseudomonas aeruginosa is a widespread Gram-negative opportunistic pathogen in environmental and hospital settings, frequently causing respiratory diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disorder (COPD) and ventilator-associated pneumonia. In our previous study, a galU-deleted clinical P. aeruginosa was found to exhibit increased susceptibility to polymyxins. The galU gene plays an important role in the biosynthesis of lipopolysaccharide (LPS) O-antigen. Here, we systematically evaluated the effects of galU deletion on the phenotype and virulence of P. aeruginosa PAO1. A galU deletion mutant was successfully constructed in P. aeruginosa PAO1 by CRISPR/Cas9, and the complementation was accomplished by pUCP18 plasmid carrying wildtype galU. The changes in phenotype, virulence and pathogenicity were systemically studied. The results revealed that knockout of galU led to the loss of O-antigen, which affected growth, virulence and pathogenicity through various ways in P. aeruginosa, and significantly affected the susceptibility of P. aeruginosa to polymyxins. Mechanism study suggested the involvements of quorum sensing, Entner-Doudoroff pathway and tyrosine metabolism, etc on bacterial virulence, antibiotic susceptibility changes after galU deletion. galU and the related pathways may serve as effective targets for treatment of P. aeruginosa infection, providing a theoretical basis for the development of novel antibacterial drugs.
2026-06-25 | Salvage Treatment of Ventilator-Associated Pneumonia Using Sulbactam-Durlobactam in a Preterm Neonate: A Case Report.
Ventilator-associated pneumonia (VAP) is a leading cause of nosocomial infections in neonatal intensive care units (NICUs) and is associated with significant morbidity, mortality, and prolonged hospitalization, particularly in preterm neonates. Management is complicated by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens, with very limited evidence supporting the use of reserve antibiotics in this population. We report a male neonate born at 25 weeks of gestation (birth weight 740 g) who developed severe VAP caused by XDR Acinetobacter calcoaceticus-baumannii complex and Pseudomonas aeruginosa. After failure of multiple antibiotic regimens, including ampicillin, amikacin, meropenem, vancomycin, cefepime with inhaled colistin, tigecycline, and ceftazidime-avibactam combined with fosfomycin, the infant was treated with sulbactam-durlobactam (25 mg/kg/dose every 6 h) in combination with ceftazidime-avibactam. After 12 days of this regimen, the neonate was successfully extubated. This case highlights the therapeutic challenges of XDR infections in extremely preterm neonates and suggests that sulbactam-durlobactam may represent a viable salvage treatment option. Further pharmacokinetic and clinical studies are needed to establish optimal dosing and safety in the neonatal population.
proteins
2026-04-23 | Marine antimicrobial peptide scyreprocin exhibits therapeutic potential against multidrug-resistant bacteria in wound and lung infections with low resistance.
Antibiotic resistance, driven by multidrug-resistant (MDR) pathogens, poses a major global health threat. Antimicrobial peptides (AMPs) have garnered significant attention as promising therapeutic agents for combating MDR bacteria. Here, we demonstrate the potent antimicrobial activity of scyreprocin against MDR strains, including Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Notably, scyreprocin eradicated the tested strains without inducing drug resistance, inhibited biofilm formation, and eliminated persister cells. In terms of in vivo efficacy, scyreprocin displayed excellent activity against S. aureus and K. pneumoniae in a full-thickness wound infection model. Furthermore, administration of scyreprocin reduced bacterial burden in a K. pneumoniae lung infection model, thereby attenuating the pulmonary inflammatory response. Crucially, under cumulative administration of 25 mg/kg for 5 days, scyreprocin treatment via intravenous injection exerted no in vivo toxicity to mice. Mechanistic studies indicated that scyreprocin triggered membrane damage by causing rapid membrane permeability and leakage. Taken together, the marine-sourced scyreprocin demonstrates effective therapeutic potential for treating infections caused by drug-resistant pathogens.
2026-03-25 | Antimicrobial Peptides and ESKAPEE Pathogens: A New Frontier in the Fight Against Antimicrobial Resistance.
Antimicrobial resistance is the most critical global health challenge, largely complicating the treatment of infections caused by multi-drug-resistant pathogens. Among them, ESKAPEE pathogens comprise Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli, which emerged as significant pathogens due to their ability to evade conventional antibiotics. These pathogens cause millions of infections and thousands of deaths every year, mainly in the healthcare sector. Their resistance mechanisms may include modification of targets for antibiotics, increased efflux pump activity, decreased influx, and inactivation of antibiotics. Antimicrobial peptides (AMPs) represent a new candidate whose broad-spectrum activity against microorganisms often protects against susceptible pathogens. AMPs, naturally present in most living organisms as part of innate immunity, are now synthetically produced to harness their antimicrobial properties in therapeutic applications. Moreover, their mechanisms of action make them unique and capable of circumventing the classical resistance pathways. Thus, they offer hope in combating ESKAPEE pathogens. This review discusses the prevalence and clinical significance of ESKAPEE pathogens, their resistance mechanisms, and the possible roles of AMPs in developing effective therapy. With these escalating trends in AMR globally, understanding their dynamics is of prime importance to improve infection control measures and patient outcomes in critical care environments. In addition to an overview of available information on the biology and drug-resistance mechanisms of these pathogens, the review also evaluates the antimicrobial activity of AMPs against multidrug-resistant bacteria, discusses their benefits compared to traditional antibiotics, and highlights significant drawbacks that could limit their clinical use.
2026-02-26 | Pharmacodynamic evaluation of BRII-693, a next-generation synthetic macrocyclic peptide antibiotic, in the neutropenic mouse thigh and lung infection models against gram-negative pathogens.
BRII-693 is a next-generation synthetic macrocyclic peptide antibiotic for infections caused by drug-resistant gram-negative pathogens. This study evaluated the pharmacodynamic activity of BRII-693 against common gram-negative pathogens using neutropenic mouse thigh (11 strains) and lung (15 strains) infection models. BRII-693 exhibited dose-dependent increases in pharmacokinetic exposure in both plasma and epithelial lining fluid (ELF). Due to its prolonged elimination half-life within ELF, the ELF area under the curve (AUC) was higher than plasma AUC on a mg/kg basis. In dose-ranging PK/PD studies, BRII-693 demonstrated dose-dependent antibacterial activity. In both the thigh and lung models, bacterial stasis was achieved at 24 h plasma AUC/MIC values of 1-19 for Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, and 1-log kill required only modestly higher targets given the steep exposure-response relationships. Higher target exposures were noted for Pseudomonas aeruginosa studies. In the lung model, BRII-693 achieved robust cidal endpoints against all tested organisms. Maximal effect (3-4 log reduction in bacterial burden) converged at a 24 h plasma AUC/MIC value of 50. These findings demonstrate robust PK/PD profile and in vivo efficacy of BRII-693 against clinically relevant gram-negative pathogens, supporting its potential as a next-generation macrocyclic peptide antibiotic.
2026-02-24 | Myeloid-derived interleukin-10 induced by thrombospondin-1 mediates host defense and regulates inflammation during acute bacterial lung infection
ABSTRACT Pseudomonas aeruginosa ( P. aeruginosa ) is a leading cause of hospital- and ventilator-associated pneumonia, driven by virulence factors that damage lung tissue. Neutrophils and monocytes are myeloid immune cells that play key roles in host defense during pulmonary infection against P. aeruginosa ; although if not properly regulated, their inflammatory activity can lead to severe lung injury. Thrombospondin-1 (TSP-1) is a host glycoprotein that regulates neutrophil activation in the lungs during P. aeruginosa infection, protecting the host from mortality. Here, we demonstrate that in addition to regulating the pro-inflammatory phenotype of neutrophils, during P. aeruginosa infection, TSP-1 induces IL-10 in the lung tissue of mice inoculated with this bacterium. Our data show that neutrophils and Ly6C + monocytes are major sources of lung IL-10 during the first 48 h post-infection, a cytokine that is required for host survival, host defense, and to reduce lung inflammation and injury. Further in vitro studies determined that TSP-1 induces IL-10 production in lipopolysaccharide-stimulated CD11b + Ly6G + Ly6C + cells differentiated from bone marrow precursors through a mechanism dependent on the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Importantly, intratracheal transfer of IL-10 +/+ CD11b + Ly6G + Ly6C + cells 1 day before infection to Thbs1 −/− mice restored their ability to produce IL-10 in the lungs, improved host defense, and reduced lung inflammation and permeability upon infection. Altogether, our data show that TSP-1 induces IL-10 production in neutrophils and monocytes, enhancing host defense while reducing lung inflammation.
2025-11-18 | Engineered Mycoplasma pneumoniae targeting dual-species bacterial biofilms: a novel strategy against infections.
Antimicrobial resistance is a major global health threat, potentially causing 8.22 million deaths annually by 2050. Polymicrobial biofilms significantly contribute to this crisis, leading to treatment failure, especially in chronic airway infections caused by Staphylococcus aureus and Pseudomonas aeruginosa, common in ventilator-associated pneumonia and cystic fibrosis. To address this, we engineered an attenuated Mycoplasma pneumoniae strain, CV8_HAD, to secrete biofilm-disrupting enzymes (PelAh, PslGh, A1-II' and Dispersin B). CV8_HAD showed strong in vitro activity against single and mixed-species biofilms of S. aureus and P. aeruginosa, and demonstrated in vivo efficacy against S. aureus biofilms in mice and mixed infections in Galleria mellonella larvae. This study establishes engineered M. pneumoniae as a promising therapeutic strategy for tackling microbial biofilms and highlights the potential of G. mellonella larvae models as an alternative to mouse models in advancing research on biofilm-targeting interventions.
vaccines
2025-07-25 | Development of a bivalent protein subunit vaccine against infection by Pseudomonas aeruginosa and Staphylococcus aureus
Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA) are members of the ESKAPE pathogens, a group of bacteria that are a threat to human health due to their ability to resist antibiotics. They are known to cause severe infections, often as co-morbidities, in individuals with conditions such as people with cystic fibrosis, diabetes, wounds, pneumonia, and critically ill patients requiring intubation leading to ventilator-associated pneumonia. Emergence of multi-drug resistance in SA and PA is making traditional antibiotic treatment ineffective and unfortunately there are no licensed vaccines to prevent MRSA or PA infections. We have demonstrated that when delivered intranasally (IN) L-PaF, a genetic fusion of the PA type III secretion system (T3SS) proteins PcrV and PopB (PaF) with LTA1, the active moiety of heat-labile enterotoxin from enterotoxigenic E. coli, protects against PA. L-PaF was formulated as a nanoemulsion (ME) to increase the protective immune response against clinically relevant PA strains in a mouse lung colonization model. With the addition NEAT2, the heme capturing domain of the SA protein IsdB, a bivalent vaccine was generated. IN administration of the bivalent formulation protected MRSA pre-exposed mice from both MRSA and PA infection. Sera from mice vaccinated with our formulation contained strong IgG titers with high levels of opsonophagocytic killing of homologous and heterologous PA and SA strains. Additionally, the bivalent L-PaF/NEAT2 formulation elicited stimulation of IL-17A and IL-2 cytokines. Because established PA and SA lung infection models with rabbits better reproduce the clinical hallmarks of severe human acute pneumonia, rabbits were immunized with the bivalent L-PaF/NEAT2 formulation. All of the vaccinated rabbits survived the challenges while the controls did not. These findings demonstrate that our L-PaF/ME/NEAT2 formulation has potential as a broad-spectrum vaccine against both SA and PA infection.
2025-07-06 | In silico development of a broad-spectrum vaccine against ESKAPE pathogens.
Antimicrobial-resistant ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae) have significantly restricted therapeutic alternatives for critical infections, consequently contributing to increase the severity and mortality of infectious illnesses that represent a significant global health challenge. Vaccination as a preventive measure can be crucial in substantially reducing bacterial infections and is potentially effective against antibiotic-resistant bacteria. This study shows the design of an epitope-based vaccine capable of neutralizing shared antigenic determinants present among the ESKAPE pathogens. The pangenome of the ESKAPE pathogens was analyzed to extract the core proteome. This approach facilitated reverse vaccinology analysis to identify antigenic proteins within this bacterial group. The study revealed similar structures in porins OmpA, OprD, and TolC, as well as the collagen-binding adhesins Acm and Cna. These proteins were then utilized to predict T-cell and B-cell epitopes, selecting those with their best physicochemical properties, antigenicity, non-allergenicity, and lack of toxicity. Additionally, epitopes located on the surface of the antigens and capable of coupling with HLA molecules were prioritized. In this computational approach, we engineered a construct incorporating the adjuvant RS09, a TLR4 agonist, and immunogenic epitopes connected by linkers. We assessed the stability of their interaction with pattern recognition receptors of the immune system through molecular docking and molecular dynamics simulations. The in silico immune simulation demonstrated that the vaccine could trigger humoral and cell-mediated immune responses. The resulting construct potentially represents an effective and safe vaccine candidate to prevent infections caused by the ESKAPE group.
2024-12-25 | Hybrid Cell Membrane-Engineered Nanocarrier for Triple-Action Strategy to Address Pseudomonas aeruginosa Infection.
Bacterial infections resistant to antimicrobial treatments, particularly those caused by Pseudomonas aeruginosa (P. aeruginosa), frequently lead to elevated mortality rates. Tackling this resistance using therapeutic combinations with varied mechanisms has shown considerable promise. In this study, a bioinspired nanocarrier is successfully designed and engineered for targeted antibiotic delivery and toxin/bacteria clearance. This is achieved by encapsulating antibiotic-loaded framework nucleic acids with hybrid cell membranes acquired from neutrophils and platelets. By coating the hybrid membrane outside the shell, nanocarriers are endowed with the function of neutrophil-like chemotaxis and platelet-like bacteria adhesion to achieve the first stage of inflammation targeting. Based on the specific binding of bacteria toxin to the hybrid membrane, the release of antibiotic-loaded framework nucleic acids is triggered by toxin-mediated membrane lysis to fulfill the second stage of toxin neutralization and bacteria killing. Meanwhile, the immunomodulation potential of framework nucleic acids enables nanocarriers to accomplish the third stage of reversing the immunosuppressive microenvironment. In mouse models of acute and chronic P. aeruginosa pneumonia, the nanocarriers can reduce bacterial burden at a low dosage and decrease mortality with negligible toxicity. In sum, these findings have illustrated the remarkable capability of nanocarriers in treating recalcitrant bacterial infections.
2024-11-18 | Mucosal immunization with the lung Lactobacillus-derived amphiphilic exopolysaccharide adjuvanted recombinant vaccine improved protection against P. aeruginosa infection.
Respiratory infections caused by Pseudomonas aeruginosa are a major health problem globally. Current treatment for P. aeruginosa infections relies solely on antibiotics, but the rise of antibiotic-resistant strains necessitates an urgent need for a protective vaccine. Traditional parenteral vaccines, despite employing potent adjuvants aimed at serotype-dependent immunity, often fail to elicit the desired mucosal immune response. Thus, developing vaccines that target both localized mucosal and systemic immune responses represents a promising direction for future research on P. aeruginosa vaccination. In this study, we explored EPS301, the exopolysaccharide derived from the lung microbiota strain Lactobacillus plantarum WXD301, which exhibits excellent self-assembly properties, enabling the formation of homogeneous nanoparticles when encapsulating recombinant PcrV of P. aeruginosa, designated as EPS301@rPcrV. Notably, the EPS301 vector effectively enhanced antigen adhesion to the nasal and pulmonary mucosal tissues and prolonged antigen retention. Moreover, EPS301@rPcrV provided effective and sustained protection against P. aeruginosa pneumonia, surpassing the durability achieved with the "gold standard" cholera toxin adjuvant. The EPS301-adjuvanted vaccine formulation elicited robust mucosal IgA and Th17/γδ17 T cell responses, which exceeded those induced by the CTB-adjuvanted vaccination and were sustained for over 112 days. Additionally, Th 17 and γδ 17 resident memory T cells induced by EPS301@rPcrV were crucial for protection against P. aeruginosa challenge. Intriguingly, IL-17A knockout mice exhibited lower survival rates, impaired bacterial clearance ability, and exacerbated lung tissue damage upon EPS301 adjuvanted vaccination against P. aeruginosa-induced pneumonia, indicating an IL-17A-dependent protective mechanism. In conclusion, our findings provided direct evidence that EPS301@rPcrV mucosal vaccine is a promising candidate for future clinical application against P. aeruginosa-induced pulmonary infection.
2023-11-01 | A protein-free vaccine stimulates innate immunity and protects against nosocomial pathogens.
Traditional vaccines are difficult to deploy against the diverse antimicrobial-resistant, nosocomial pathogens that cause health care-associated infections. We developed a protein-free vaccine composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan that improved survival and reduced bacterial burden of mice with invasive blood or lung infections caused by methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, extended-spectrum beta-lactamase-expressing Escherichia coli, and carbapenem-resistant strains of Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The vaccine also conferred protection against the fungi Rhizopus delemar and Candida albicans. Efficacy was apparent by 24 hours and lasted for up to 28 days after a single vaccine dose, with a second dose restoring efficacy. The vaccine acted through stimulation of the innate, rather than the adaptive, immune system, as demonstrated by efficacy in the absence of lymphocytes that were abrogated by macrophage depletion. A role for macrophages was further supported by the finding that vaccination induced macrophage epigenetic alterations that modulated phagocytosis and the inflammatory response to infection. Together, these data show that this protein-free vaccine is a promising strategy to prevent deadly antimicrobial-resistant health care-associated infections.
gene therapies
2026-06-27 | Inhalable bacteriophage endolysins: a novel therapeutic strategy for drug-resistant bacterial pulmonary infections - a comprehensive review.
Pulmonary infections caused by multidrug-resistant (MDR) bacteria pose a severe global health threat with high mortality rates, especially in hospital-acquired pneumonia. The stagnation of new antibiotic development underscores the urgent need for alternative therapeutics. This review summarizes recent advances in the application of bacteriophage endolysins against major MDR respiratory pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. We focus on their mechanisms of action, synergistic effects with antibiotics, and efficacy against biofilms. Endolysins demonstrate potent and species-specific lytic activity against a broad spectrum of MDR bacteria. A key advantage is their low propensity for inducing resistance. Critically, when administered via optimized inhalation delivery systems, endolysins can achieve high local concentrations in the lungs - though this depends on factors such as the aerosol device, formulation properties and patient-related variables - effectively eradicating pathogens in animal models of pneumonia with minimal systemic toxicity. This direct pulmonary delivery approach bypasses many challenges associated with systemic administration and enhances therapeutic outcomes. Endolysins represent a promising paradigm shift in combating drug-resistant bacterial pulmonary infections. Their rapid lytic activity, synergy with conventional antibiotics, and suitability for inhalable formulation position them as a potent adjunct or alternative therapy. While challenges in stabilization and large-scale production remain, advancing inhalation delivery systems for endolysins holds immense potential to holds immense potential to revolutionize the treatment of recalcitrant respiratory infections.
2026-03-27 | Mapping the clinical use of inhaled bacteriophages in respiratory infections caused by multidrug-resistant pathogens: a scoping review.
Inhaled bacteriophage therapy is an emerging adjunctive strategy for treating lower respiratory tract infections caused by multidrug-resistant (MDR) pathogens. However, the clinical evidence base remains fragmented. We conducted a scoping review to map the current landscape of human studies using nebulized, aerosolized, or dry-powder phage therapy for pulmonary infections. We systematically searched PubMed, Scopus, Web of Science, and ClinicalTrials.gov for clinical studies published up to 1 June 2025. Eligible studies included clinical trials, cohort studies, and case reports/series reporting at least one dose of inhaled lytic phage for bacterial respiratory infections. Screening followed PRISMA-ScR guidelines. Key data were extracted on patient characteristics, pathogens, phage preparations, delivery methods, safety, and outcomes. Of 507 records identified, 31 studies met inclusion criteria: six clinical trials and 25 case reports or series. Target infections included ventilator-associated pneumonia, cystic fibrosis exacerbations, and chronic bronchiectasis, primarily due to Pseudomonas aeruginosa, Acinetobacter baumannii, or Klebsiella pneumoniae. Delivery methods varied widely, including nebulizers, dry-powder inhalers, and endotracheal instillation. Most studies reported clinical or microbiological improvement without major adverse events, though few used standardized outcome measures. Inhaled phage therapy has shown promise in compassionate and investigational settings for MDR respiratory infections. Despite heterogeneity in delivery methods and outcome reporting, preliminary data suggests feasibility and safety. Standardized protocols and controlled trials are needed to define its role in pulmonary antimicrobial therapy.
2026-02-22 | <b>Evaluating a Novel Bacteriophage Cocktail for Eradicating Pseudomonas aeruginosa Biofilms in Ventilator-Associated Pneumonia</b>
Background: Ventilator-associated pneumonia caused by Pseudomonas aeruginosa remains difficult to treat because of multidrug resistance and biofilm formation, which reduce antibiotic penetration and contribute to persistent infection in mechanically ventilated patients. Objective: To evaluate the efficacy of adjunctive nebulized bacteriophage cocktail therapy in reducing P. aeruginosa biofilm burden and improving microbiological and clinical outcomes in ventilator-associated pneumonia. Methods: A parallel-group randomized controlled trial was conducted in tertiary care intensive care units over five months. Seventy-two mechanically ventilated adults with microbiologically confirmed P. aeruginosa ventilator-associated pneumonia and evidence of biofilm formation were randomized to receive either standard culture-guided antibiotic therapy plus nebulized bacteriophage cocktail twice daily for 14 days or standard care alone. Primary outcomes were biofilm biomass reduction and microbiological clearance; secondary outcomes included duration of mechanical ventilation, Clinical Pulmonary Infection Score, and intensive care unit stay. Results: The final analyzed cohort included 63 participants. Day-14 biofilm biomass was significantly lower in the intervention group than in controls (0.62 ± 0.18 vs 0.94 ± 0.22 OD units; p<0.001). Culture negativity was higher with bacteriophage therapy (75.0% vs 45.2%; p=0.01). The intervention group also had shorter mechanical ventilation duration, lower day-14 Clinical Pulmonary Infection Score, and reduced intensive care unit stay (p<0.05 for all). Conclusion: Adjunctive nebulized bacteriophage cocktail therapy improved biofilm reduction, microbiological clearance, and short-term clinical outcomes in P. aeruginosa ventilator-associated pneumonia.
2025-12-16 | Navigating the Crisis of Multidrug-Resistant Infections in Infants to Teenagers: Regional Variability and Global Solutions
Superbacteria, or multidrug-resistant (MDR) microorganisms, pose a major global health threat, particularly in regions such as South Asia and sub-Saharan Africa. Bacteria, such as Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa, are resistant to multiple antibiotics, making infections more difficult to treat. These resistant infections cause millions of deaths annually, with vulnerable groups, such as neonates and children, being particularly at risk. The overuse of antibiotics in medicine and livestock, along with weak healthcare systems, accelerates the spread of antibiotic resistance, especially in countries such as India, China, and Pakistan. Common resistant infections include urinary tract infections, neonatal sepsis, and ventilator-associated pneumonia (VAP). Resistance to antibiotics, such as carbapenems and third-generation cephalosporins, along with the rise of ESBL-producing bacteria, complicates treatment, particularly in neonatal intensive care units (NICUs). This paper reviews global data on superbacteria, focusing on neonatal and pediatric populations, highlighting the need for better diagnostics, novel treatments (e.g., phage therapy), antimicrobial stewardship, infection control, and global cooperation to combat the growing threat of resistance.
2025-11-13 | Efficacy of Phage Cocktails Against Biofilms Formed by Antibiotic-Resistant Bacteria.
The rapid spread of multidrug-resistant strains of Klebsiella pneumoniae and Pseudomonas aeruginosa, along with their ability to form biofilms on various medical devices, significantly complicate the treatment of infections caused by these microorganisms and render antibiotic therapy ineffective. In contrast, the use of bacteriophages is a promising alternative for combating antibiotic-resistant biofilm-forming strains of K.pneumoniae and P.aeruginosa. Two cocktails of 14 bacteriophages (nine Klebsiella phages and five Pseudomonas phages) were used to control biofilms formed by XDR (Extensively Drug-Resistant) strains of K. pneumoniae and P. aeruginosa under in vitro conditions. The K. pneumoniae strain harbored genes associated with biofilm formation fimH, mrkA, matBecp and antibiotic resistance blaNDM-1, blaKPC, blaOXA-48, blaCTX-M-1, blaTEM . The P. aeruginosa strain carried genes associated with biofilm formation algD, PslD, PelF and antibiotic resistance blaNDM-1 .Bacteriophages were isolated from the wastewater samples. Biofilms were formed on various substrates (glass slides, wells of polystyrene plates, and polyvinyl chloride vascular catheters) and analyzed using optical and scanning electron microscopy, as well as gentian violet staining assays. The results demonstrated that bacteriophage cocktails could effectively degrade biofilms of K. pneumoniae and P. aeruginosa. Biofilms formed on catheter segments, polystyrene plate wells, and glass slides were treated with lytic bacteriophages at concentrations of at least 10^7 PFU/mL. After 24 h of treatment with phage cocktails, a 34.5% reduction in biofilm biomass was observed on the catheters for K. pneumoniae strain No. 361 and 34.1% for P. aeruginosa strain No. 7. In polystyrene plate wells, the reductions were 39.3% and 52.8%, respectively. The experimental results indicate the effectiveness of phage cocktails in reducing biofilm biomass and bacterial viability. Given the ability of phages to degrade biofilms, phage therapy may become a promising adjunct to standard treatment methods for infections caused by multidrug-resistant pathogens.
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2026-06-17 | Engineering low-endotoxin lipid A in a double auxotroph Pseudomonas aeruginosa to develop safer whole-cell vaccines.
Pseudomonas aeruginosa is a highly adaptable Gram-negative bacterium causing severe respiratory infections, particularly in vulnerable populations. The rise of antimicrobial resistance highlights the urgent need for effective vaccines. We previously developed a live-attenuated vaccine candidate, PAO1 ΔmurI Δalr ΔdadX, a genetically stable double auxotrophic strain that exhibited dose-dependent reactogenicity upon intranasal administration in mice, likely due to lipid A component of lipopolysaccharide (LPS). To reduce LPS-associated toxicity while preserving immunogenicity, we engineered novel strains by inactivating genes involved in lipid A biosynthesis (htrB1, htrB2) or modification (pagP, pagL). Lipid A structural modifications were confirmed by MALDI-TOF MS. Mutants were evaluated for Toll-like receptor 4 (TLR4) activation, virulence attenuation, and their ability to induce immune responses and protection in an acute pneumonia model. All engineered strains displayed modified lipid A structures. Mutations in htrB1 and htrB2 reduced TLR4 activation and significantly attenuated virulence following intraperitoneal challenge in mice. Inactivation of pagL resulted in minimal attenuation, whereas pagP inactivation led to marked attenuation without altering TLR4 activation. In the acute pneumonia model, all mutants elicited robust systemic and mucosal immune responses, and conferred strong protection, despite transient weight loss following intranasal administration. Targeted lipid A modification represents an effective strategy to reduce in vitro reactogenicity while preserving immunogenicity in live-attenuated P. aeruginosa vaccine candidates. Although further optimization may minimize residual in vivo effects, these findings support the potential of engineered strains as vaccine candidates for preventing respiratory infections caused by P. aeruginosa.
2026-06-17 | Engineered antibodies bypass bacterial immune evasion to drive complement-mediated protection against lethal infections.
The expanding global crisis of bacterial infections caused by antimicrobial-resistant pathogens has resulted in an urgent need for therapeutics. Previous efforts to target pathogen surface antigens with monoclonal antibodies (mAbs) have sought to activate the complement system, primarily through the antibody-dependent classical pathway. However, most mAbs have induced insufficient complement activation because pathogen evasion strategies disrupt the complex spatiotemporal requirements for activation of the classical pathway initiation complex C1. To address this, we developed a targeted complement activation therapy (T-CAT), which uses antibodies furnished with the enzymatic capability to initiate complement activation directly on the bacterial surface without involvement of the classical pathway initiation complex. We found that T-CAT mAbs directed against bacterial surface antigens can overcome the strategies that pathogens evolved to escape from classical pathway-mediated clearance by the immune system. We further demonstrated that T-CAT mAbs could safely and effectively be used to treat infectious disease in experimental murine models of sepsis and pneumonia caused by Klebsiella pneumoniae, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Neisseria meningitidis. Together, these data highlight the potential for T-CAT as a next-generation mAb platform with broad applicability against diverse microbial species, including multidrug-resistant pathogens, without promoting drug resistance.
2026-06-12 | AZinc-Coordinated Glycopolymer for Inhibiting BacterialToxins in Management of Acute Pneumonia
Bacterial toxins play a critical role in infections by compromising host defenses, causing host cell death, and inducing excessive immune activation, ultimately leading to severe tissue damage and increased mortality. To combat both the pathogen and its associated toxins, this study developed a bacteria-targeting zinc-coordinated glycopolymer designed to deliver antisense oligonucleotides (ASOs) and absorb lipopolysaccharides (LPS). The functional polymer enhances Pseudomonas aeruginosa internalization efficiency through galactose-mediated bacterial surface interaction. By delivering multiple ASOs, the nanoparticle enables the dual suppression of bacterial growth and quorum sensing, exhibiting potent antibacterial activity. Furthermore, zinc ions coordinated within the glycopolymer impart the ability to bind and adsorb LPS, thereby mitigating the toxin-induced damage to host cells. In a murine model of acute pneumonia, this approach significantly improved survival rates and reduced pro-inflammatory cytokine levels. Consequently, pulmonary inflammation was suppressed, bacterial toxin-induced damage was alleviated, and tissue integrity was preserved. This synergistic strategy of combined sterilization and toxin neutralization offers a novel and synergistic therapeutic approach to combating bacterial infections.
2026-06-01 | Data Sheet 1_Engineering low-endotoxin lipid A in a double auxotroph Pseudomonas aeruginosa to develop safer whole-cell vaccines.pdf
Introduction Pseudomonas aeruginosa is a highly adaptable Gram-negative bacterium causing severe respiratory infections, particularly in vulnerable populations. The rise of antimicrobial resistance highlights the urgent need for effective vaccines. We previously developed a live-attenuated vaccine candidate, PAO1 ΔmurI Δalr ΔdadX, a genetically stable double auxotrophic strain that exhibited dose-dependent reactogenicity upon intranasal administration in mice, likely due to lipid A component of lipopolysaccharide (LPS). Methods To reduce LPS-associated toxicity while preserving immunogenicity, we engineered novel strains by inactivating genes involved in lipid A biosynthesis (htrB1, htrB2) or modification (pagP, pagL). Lipid A structural modifications were confirmed by MALDI-TOF MS. Mutants were evaluated for Toll-like receptor 4 (TLR4) activation, virulence attenuation, and their ability to induce immune responses and protection in an acute pneumonia model. Results All engineered strains displayed modified lipid A structures. Mutations in htrB1 and htrB2 reduced TLR4 activation and significantly attenuated virulence following intraperitoneal challenge in mice. Inactivation of pagL resulted in minimal attenuation, whereas pagP inactivation led to marked attenuation without altering TLR4 activation. In the acute pneumonia model, all mutants elicited robust systemic and mucosal immune responses, and conferred strong protection, despite transient weight loss following intranasal administration. Discussion Targeted lipid A modification represents an effective strategy to reduce in vitro reactogenicity while preserving immunogenicity in live-attenuated P. aeruginosa vaccine candidates. Although further optimization may minimize residual in vivo effects, these findings support the potential of engineered strains as vaccine candidates for preventing respiratory infections caused by P. aeruginosa.
2026-05-13 | Current prospects in the development of vaccines against pseudomonas aeruginosa
Pseudomonas aeruginosa is an opportunistic pathogen with a multidrug-resistant profile that has become a critical threat to global public health. It is one of the leading causes of severe healthcare-associated infections, including ventilator-associated pneumonia, chronic infections in patients with cystic fibrosis, and bloodstream infections in immunosuppressed individuals. The development of vaccines against P. aeruginosa represents a major challenge due to the high capacity of this bacterium to form biofilms, its broad arsenal of virulence factors, and its ability to evade the host immune system. Producing a successful vaccine against P. aeruginosa may be possible in the near future through the use of multivalent strategies, including advanced technologies such as nanotechnology and RNA-based platforms, and by acquiring more detailed knowledge regarding host-pathogen interactions.
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Drug Discovery Landscape
8 orphan drug designations for Pneumonia caused by Pseudomonas aeruginosa infection.
8 orphan drug designations for Pneumonia caused by Pseudomonas aeruginosa infection.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Human monoclonal antibody IgM directed against Pseudomonas aeruginosa serotype O1 O-polysaccharide [KBPA 104] | antibodies | EMA | 2010-01-28 | — | Envestia Limited |
human monoclonal antibody directed against serotype O1 Pseudomonas aeruginosa | antibodies | FDA | 2010-01-06 | — | Kenta Biotech Limited |
Tobramycin [Vantobra] | small molecules | EMA | 2009-02-27 | — | Pari Pharma GmbH |
Human monoclonal antibody directed against serotype 011 Pseudomonas aeruginosa | antibodies | FDA | 2006-09-18 | — | Kenta Biotech Limited |
Human monoclonal antibody against Pseudomonas aeruginosa serotype O11 | antibodies | EMA | 2006-06-29 | — | Marcello Menapace |
Tobramycin [Fluidosomes Tobramycin] | small molecules | EMA | 2006-04-11 | — | [INACTIVE] Axentis Phama Limited |
Tobramycin [Tobi Podhaler] | small molecules | EMA | 2003-03-17 | — | Viatris Healthcare Limited |
Pseudomonas aeruginosa octavalent conjugated vaccine [Aerugen] | vaccines | EMA | 2001-12-11 | — | Recordati Rare Diseases |
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