RARE DISEASE
Invasive infections due to vancomycin-resistant enterococci
Invasive infections due to vancomycin-resistant enterococci
Invasive infections due to vancomycin-resistant enterococci
Synonyms: Invasive infections due to VRE
Synonyms: Invasive infections due to VRE
Synonyms: Invasive infections due to VRE
Drug discovery
1
drug
With orphan designation
Overview
Invasive vancomycin-resistant enterococci (VRE) infections, primarily caused by Enterococcus faecium and faecalis, are healthcare-associated infections marked by multidrug resistance. They occur most frequently in immunocompromised patients or those with breached anatomical barriers (e.g., catheters, surgical wounds). Common presentations include bacteremia, endocarditis, urinary tract infections, and intra-abdominal infections. Treatment is limited by resistance to vancomycin and other antibiotics, requiring tailored regimens and strict infection control [1][6][13].
Burden
In 2017, VRE caused 54,500 U.S. hospitalizations and 5,400 deaths, with $539 million in attributable costs [2][6].
Mortality rates for invasive VRE infections range from 23–65%, significantly higher than vancomycin-susceptible strains [9][14].
Prolongs hospital stays by 6 days on average and increases ICU admission risk (RR: 2.25) [6][14].
Therapies
First-line agents: Linezolid, daptomycin, and teicoplanin (in regions where susceptible).
Combination therapy: High-dose ampicillin with aminoglycosides or synergistic β-lactams for susceptible strains [3][8][13].
Emerging resistance to linezolid and daptomycin necessitates antimicrobial stewardship and susceptibility testing [3][8].
Categories: rare infectious diseases
Research Papers
450 drug discovery papers about Invasive infections due to vancomycin-resistant enterococci, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
450 drug discovery papers about Invasive infections due to vancomycin-resistant enterococci, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-01 | Characterization of vancomycin-resistant Enterococcus faecium in children admitted to a pediatric oncology hospital in the city of São Paulo Brazil
Abstract Background Vancomycin-resistant Enterococcus (VRE) is an important microorganism in nosocomial infections in pediatric oncology patients. Immunosuppression, prolonged use of antimicrobials (particularly cephalosporins and vancomycin) and invasive procedures are the main risk factors for acquiring infection by this agent. Furthermore, studies have shown that exposure of a patient bed previously occupied by a VRE carrier can be considered a risk factor for acquiring new in-patient infections. The aim of this study was to evaluate the colonization of Enterococcus faecium vancomycin- resistant (EfmVRE) and further infection in children admitted to a reference pediatric oncology hospital. Methods Retrospective cohort study conducted at a reference pediatric oncology hospital in Sao Paulo, Brazil and the Federal University of Sao Paulo. Inclusion criteria: samples from patients who were followed up during the period from January to December 2009 and who presented a positive surveillance culture for EfmVRE with a later positive clinical culture for the same agent were included in the study. We analyzed 10 samples of EfmVRE in 2009, two samples from each patient: one representative of colonization site and another of the site of infection using the analysis of the profile generated after chromosomal restriction digestion (SmaI) of the samples by PFGE, then analyzed byBioNumerics ® software, according to the microrestriction pattern obtained. Results We observed that five pediatric patients were colonized (3 rectal swabs, 1 IV catheter and 1 tracheal aspirate) by EfmVRE, and subsequently developed bloodstream infection by the same agent. We also observed a genetic similarity among representative samples of infection and colonization, from the same patient, except the patient 2. Genetic clonal profiles were observed (100% similarity) between samples isolated from patient 1 and patient 5. 95.7% similarity was observed in samples from patient 3 and 90.9% in samples of patient 4. An important fact is that patients 1, 2 and 5 were admitted to the pediatric ICU within two months period, this might explain the genetic similarity observed among the respective isolates. The finding of clonal samples as demonstrated in our study suggests that patients presenting EfmVRE colonization prior to associated risk factors developed infection due to these microorganisms. Conclusions It was also observed that there was a high degree of similarity (> 80%) among isolates from different patients and from different hospitals belonging to the same hospital complex. Earlier detection of EfmVRE colonizing patients could prevent its spreading in the hospital. In fact, two vulnerable patients died, one treated for a bloodstream infection with linezolid. Our findings point to the need of studies for EfmVR decolonization in susceptible patient to prevent further infection.
2026-07-13 | Long-Acting Lipoglycopeptide Treatment of Invasive Gram-Positive Infections.
Gram-positive infections continue to pose a therapeutic challenge owing to their invasive nature (e.g., Staphylococcus aureus and Streptococcus pyogenes) and eradication difficulties (e.g., methicillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant enterococci [VRE]). Long-acting lipoglycopeptides (laLGPs) present an effective and conveniently dosed option for the treatment of most invasive Gram-positive pathogens. Improved compliance monitoring associated with their infrequent intravenous dosing, that is not available to such degree with more frequently dosed antimicrobials outside of inpatient settings, is another benefit of laLGPs over more frequently dosed antimicrobials. In this article, we provide a narrative review, including the pharmacological characteristics of dalbavancin (DAL) and oritavancin (ORI), the only currently available laLGPs, as well as their approved and "off-label" use reported in the literature to date. We discuss their respective mechanism of action, caveats in compartments where they do not achieve sufficient concentrations (i.e., central nervous system [CNS]; potentially pneumonias with ORI), as well as their reported efficacy in individual organ systems as reported in literature. Lastly, we summarize insights about laLGP use in special populations and discuss the benefits of therapeutic drug monitoring of these agents, mainly in conditions requiring prolonged therapy (e.g., hardware-associated orthopedic infections).
2026-01-01 | Clinical, genomic, and functional characterization of vancomycin-resistant Enterococci from immunocompromised patients: insights into epithelial dysfunction and bloodstream infections.
Vancomycin-resistant Enterococcus faecium and Enterococcus faecalis (VRE) are increasingly recognized as major opportunistic pathogens in immunocompromised patients, where they may cause bloodstream infections (BSIs). The present study aimed to characterize a cohort of immunocompromised patients colonized or infected with VRE, performing genomic analysis of these isolates. Additionally, we investigated the impact of bacterial culture supernatants on Caco-2 epithelial cells, focusing on adhesion and cytotoxicity to elucidate mechanisms related to epithelial dysfunction and bacterial translocation. We conducted a retrospective study including 46 VRE from two Italian hospitals. Clinical and epidemiological data were collected, and isolates were characterized by antimicrobial susceptibility testing and whole-genome sequencing. Four representative isolates (E. faecium ST80, E. faecium ST117, E. faecalis ST28, and E. faecalis ST179) and two reference strains (ATCC 29212™ and ATCC 51299™) were selected for in vitro analyses. Adhesion to Caco-2 monolayers was quantified, while cytotoxicity was assessed using MTT assays with bacterial cell-free supernatants (CS). Hydrogen peroxide (H2O2) production was measured using the Amplex® Red Hydrogen Peroxide/Peroxidase Assay Kit. The majority of isolates were E. faecium (78.3%), predominantly ST80 and ST117, possessed multiple resistance determinants. E. faecalis isolates displayed greater sequence type diversity with a ST28 predominance, carrying virulence genes as ebp, gelE, and elrA. In vitro, bloodstream-derived isolates (E. faecium 51, E. faecalis 52) and reference strain ATCC 29212™ adhered more strongly to Caco-2 cells than other isolates. CS from invasive isolates and ATCC 51299™ significantly reduced epithelial cell viability at 24 h (p < 0.01). In these isolates, H2O2 higher quantification was documented in a cellular model. Our findings highlighted the convergence of antimicrobial resistance and virulence traits in VRE, alongside functional evidence of strain-dependent adhesion and secretion of cytotoxic metabolites. Elevated H2O2 production provides a possible path between enterococcal secretomes and epithelial injury, suggesting oxidative stress as a contributor to epithelial dysfunction and potential translocation. These insights expand current understanding of VRE pathogenesis and point to novel therapeutic approaches aimed at preserving epithelial integrity and mitigating oxidative damage in high-risk patients.
2025-10-02 | Impact of the COVID-19 pandemic on vancomycin-resistant Enterococcus bloodstream infections: a 6-year study in Western Greece
Background Antimicrobial resistance is a critical and growing global health concern. While drug-resistant Gram-negative bacilli pose a significant threat, multidrug-resistant Gram-positive bacteria—such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and β-lactamase-resistant Streptococcus pneumoniae —also present serious clinical challenges. Aim This study provides an epidemiological analysis of resistant Gram-positive bacteria, focusing on VRE, at a tertiary university hospital in Western Greece from 2018 to 2023. Results A total of 276 blood cultures with vancomycin-resistant Enterococcus spp. were recorded. A significant increase in VRE prevalence was observed in intensive care units (ICUs), with cases rising from 4 in 2020 to 36 in 2021. A broader increase across medical and surgical wards was noted in 2022–2023. Linezolid resistance remained low throughout the study period. Mortality data revealed a marked increase in deaths after 2020 compared to 2018–2019, coinciding with the rise in VRE-related bloodstream infections. The Coronavirus Disease 2019 (COVID-19) pandemic was associated with higher VRE rates in ICU patients, likely due to prolonged hospitalizations, increased use of invasive devices, and broad-spectrum antibiotic use. Resistance rates to both linezolid and tigecycline remained low, while daptomycin resistance showed an increasing trend the same period. Conclusion The number of VRE increased over the study period. Linezolid and tigecycline remained largely effective, but emerging resistance patterns—particularly to daptomycin—underscore the urgent need for strengthened antimicrobial stewardship and the development of novel therapeutic options to address rising resistance among Gram-positive pathogens.
2025-09-21 | A risk-based assessment of Enterococcal Bloodstream infection: Suggesting considerations in empirical therapy strategies in a tertiary care hospital.
Enterococcal bloodstream infections (E-BSIs) pose a significant challenge due to their unique intrinsic and increasing resistance. Empirical treatment guidelines are often ineffective in E-BSI, as Antibiotic policies mainly address Gram-negative bacilli and MRSA for Hospital-acquired infection (HAI) in India. The study was designed to investigate the risk factors, infection source, species profile, antimicrobial susceptibility and clinical outcomes in diagnosed E-BSI patients at a tertiary care centre in India. From the blood culture samples from August 2022 to July 2023, 52 non-duplicate blood culture isolates of Enterococcus species were identified with categorisation of vancomycin resistance genes, and the patients were followed up for risk factors, probable sources, and ongoing therapies, with a switch to definitive therapy for the outcome. Of 52 confirmed E-BSI cases, the species distribution was as follows: E. faecium (61.5 %), E. faecalis (26.92 %), E. gallinarum (9.61 %), and E. durans (1.92 %). Antimicrobial resistance was significantly higher in E. faecium. Nine isolates (17.3 %) were vancomycin-resistant enterococci (VRE), with diverse outcomes. HAI comprised 44.23 % of cases. The overall mortality rate was 26.9 % and ICU patients had significantly higher mortality, with significant risk factors being invasive medical devices (59.6 %), followed by bedridden status (23 %) and immunosuppression (9.61 %). Significant risk factors included the presence of invasive medical devices (59.6 %), followed by a bedridden status (23.0 %) and immunosuppression (9.6 %). Patients with early empirical therapy that has enterococcal coverage showed a protective effect on survival. However, switching over to definitive therapy alone could not significantly reduce mortality. This study underscores the importance of early empirical therapy with enterococcal coverage in high-risk patients. Timely initiation of empirical coverage appears more crucial than later definitive therapy adjustments in improving survival. Invasive device use remains a significant risk factor, reinforcing the need for stringent infection control to prevent HAI, including E-BSI.
proteins
2024-04-09 | A Comprehensive Review of Recent Research into the Effects of Antimicrobial Peptides on Biofilms—January 2020 to September 2023
Microbial biofilm formation creates a persistent and resistant environment in which microorganisms can survive, contributing to antibiotic resistance and chronic inflammatory diseases. Increasingly, biofilms are caused by multi-drug resistant microorganisms, which, coupled with a diminishing supply of effective antibiotics, is driving the search for new antibiotic therapies. In this respect, antimicrobial peptides (AMPs) are short, hydrophobic, and amphipathic peptides that show activity against multidrug-resistant bacteria and biofilm formation. They also possess broad-spectrum activity and diverse mechanisms of action. In this comprehensive review, 150 publications (from January 2020 to September 2023) were collected and categorized using the search terms ‘polypeptide antibiotic agent’, ‘antimicrobial peptide’, and ‘biofilm’. During this period, a wide range of natural and synthetic AMPs were studied, of which LL-37, polymyxin B, GH12, and Nisin were the most frequently cited. Furthermore, although many microbes were studied, Staphylococcus aureus and Pseudomonas aeruginosa were the most popular. Publications also considered AMP combinations and the potential role of AMP delivery systems in increasing the efficacy of AMPs, including nanoparticle delivery. Relatively few publications focused on AMP resistance. This comprehensive review informs and guides researchers about the latest developments in AMP research, presenting promising evidence of the role of AMPs as effective antimicrobial agents.
2024-03-08 | LL-37: Structures, Antimicrobial Activity, and Influence on Amyloid-Related Diseases
Antimicrobial peptides (AMPs), as well as host defense peptides (HDPs), constitute the first line of defense as part of the innate immune system. Humans are known to express antimicrobial precursor proteins, which are further processed to generate AMPs, including several types of α/β defensins, histatins, and cathelicidin-derived AMPs like LL37. The broad-spectrum activity of AMPs is crucial to defend against infections caused by pathogenic bacteria, viruses, fungi, and parasites. The emergence of multi-drug resistant pathogenic bacteria is of global concern for public health. The prospects of targeting antibiotic-resistant strains of bacteria with AMPs are of high significance for developing new generations of antimicrobial agents. The 37-residue long LL37, the only cathelicidin family of AMP in humans, has been the major focus for the past few decades of research. The host defense activity of LL37 is likely underscored by its expression throughout the body, spanning from the epithelial cells of various organs—testis, skin, respiratory tract, and gastrointestinal tract—to immune cells. Remarkably, apart from canonical direct killing of pathogenic organisms, LL37 exerts several other host defense activities, including inflammatory response modulation, chemo-attraction, and wound healing and closure at the infected sites. In addition, LL37 and its derived peptides are bestowed with anti-cancer and anti-amyloidogenic properties. In this review article, we aim to develop integrative, mechanistic insight into LL37 and its derived peptides, based on the known biophysical, structural, and functional studies in recent years. We believe that this review will pave the way for future research on the structures, biochemical and biophysical properties, and design of novel LL37-based molecules.
2024-03-01 | Exploring the feasibility of bacteriocins EntK1 and EntEJ97s in treatment of systemic VRE infections in mice
Abstract Aims Enterocins K1 and EJ97 have specific antimicrobial activity against Enterococcus faecium and Enterococcus faecalis, respectively. The aim of this study was to investigate the utility of these enterocins for in vivo treatment of systemic enterococcal infections. Methods and results The antimicrobial effect in blood was analysed and compared against the effect in saline. Colony forming unit counts revealed that the enterocins killed all the bacteria within 1 hour. Additionally, the bactericidal effect against E. faecalis was more rapid in blood, indicating a possible synergy between EntEJ97 and blood. Importantly, no enterocin resistant mutants emerged in these experiments. Injecting the enterocins intraperitoneally in an in vivo mouse model and using fluorescence and minimum inhibitory concentration determination to estimate concentrations of the peptides in plasma, indicate that the enterocins exist in circulation in therapeutic concentrations. Alanine aminotransferase detection, and haemolysis analysis indicates that there is no detectable liver damage or haemolytic effect after injection. Conclusions The study revealed that EntK1 and EntEJ97 are able to kill all bacteria ex vivo in the presence of blood. In vivo experiments determine that the enterocins exist in circulation in therapeutic concentrations without causing liver damage or haemolysis. Future experiments should test these peptides for treatment of infection in a relevant in vivo model.
2024-02-24 | Molecular Aspects of the Functioning of Pathogenic Bacteria Biofilm Based on Quorum Sensing (QS) Signal-Response System and Innovative Non-Antibiotic Strategies for Their Elimination
One of the key mechanisms enabling bacterial cells to create biofilms and regulate crucial life functions in a global and highly synchronized way is a bacterial communication system called quorum sensing (QS). QS is a bacterial cell-to-cell communication process that depends on the bacterial population density and is mediated by small signalling molecules called autoinducers (AIs). In bacteria, QS controls the biofilm formation through the global regulation of gene expression involved in the extracellular polymeric matrix (EPS) synthesis, virulence factor production, stress tolerance and metabolic adaptation. Forming biofilm is one of the crucial mechanisms of bacterial antimicrobial resistance (AMR). A common feature of human pathogens is the ability to form biofilm, which poses a serious medical issue due to their high susceptibility to traditional antibiotics. Because QS is associated with virulence and biofilm formation, there is a belief that inhibition of QS activity called quorum quenching (QQ) may provide alternative therapeutic methods for treating microbial infections. This review summarises recent progress in biofilm research, focusing on the mechanisms by which biofilms, especially those formed by pathogenic bacteria, become resistant to antibiotic treatment. Subsequently, a potential alternative approach to QS inhibition highlighting innovative non-antibiotic strategies to control AMR and biofilm formation of pathogenic bacteria has been discussed.
2024-02-23 | Study of an Enterococcus faecium strain isolated from an artisanal Mexican cheese, whole-genome sequencing, comparative genomics, and bacteriocin expression
Abstract Enterococci are ubiquitous microorganisms in almost all environments, from the soil we step on to the food we eat. They are frequently found in naturally fermented foods, contributing to ripening through protein, lipid, and sugar metabolism. On the other hand, these organisms are also leading the current antibiotic resistance crisis. In this study, we performed whole-genome sequencing and comparative genomics of an Enterococcus faecium strain isolated from an artisanal Mexican Cotija cheese, namely QD-2. We found clear genomic differences between commensal and pathogenic strains, particularly in their carbohydrate metabolic pathways, resistance to vancomycin and other antibiotics, bacteriocin production, and bacteriophage and CRISPR content. Furthermore, a bacteriocin transcription analysis performed by RT-qPCR revealed that, at the end of the log phase, besides enterocins A and X, two putative bacteriocins not reported previously are also transcribed as a bicistronic operon in E. faecium QD-2, and are expressed 1.5 times higher than enterocin A when cultured in MRS broth.
vaccines
2022-05-27 | Designing a novel multi-epitope vaccine to evoke a robust immune response against pathogenic multidrug-resistant Enterococcus faecium bacterium
Enterococcus faecium is an emerging ESKAPE bacterium that is capable of causing severe public health complications in humans. There are currently no licensed treatments or vaccinations to combat the deadly pathogen. We aimed to design a potent and novel prophylactic chimeric vaccine against E. faecium through an immunoinformatics approach The antigenic Penicillin-binding protein 5 (PBP 5) protein was selected to identify B and T cell epitopes, followed by conservancy analysis, population coverage, physiochemical assessment, secondary and tertiary structural analysis. Using various immunoinformatics methods and tools, two linear B-cell epitopes, five CTL epitopes, and two HTL epitopes were finally selected for vaccine development. The constructed vaccine was determined to be highly immunogenic, cytokine-producing, antigenic, non-toxic, non-allergenic, and stable, as well as potentially effective against E. faecium. In addition, disulfide engineering, codon adaptation, and in silico cloning, were used to improve stability and expression efficiency in the host E. coli. Molecular docking and molecular dynamics simulations indicated that the structure of the vaccine is stable and has a high affinity for the TLR4 receptor. The immune simulation results revealed that both B and T cells had an increased response to the vaccination component. Conclusively, the in-depth in silico analysis suggests, the proposed vaccine to elicit a robust immune response against E. faecium infection and hence a promising target for further experimental trials.
2017-12-20 | Physiology and Pathology of Multidrug-Resistant Bacteria: Antibodies- and Vaccines-Based Pathogen-Specific Targeting
Multidrug-resistant bacteria (MDR) are increasing rapidly and posing a global threat to mankind. Alternative strategies other than antibiotics have to be explored urgently. In this chapter, we review the current status of nonantibiotics strategies including antibody-based therapy and vaccine development for targeting Gram-positive strains (methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium) and MDR Gram-negative strains (Acinetobacter baumannii and Pseudomonas aeruginosa). Biologics-based clinical progress against these bacterial infections is updated.
2016-07-06 | How Can Vaccines Contribute to Solving the Antimicrobial Resistance Problem?
There is a growing appreciation for the role of vaccines in confronting the problem of antimicrobial resistance (AMR). Vaccines can reduce the prevalence of resistance by reducing the need for antimicrobial use and can reduce its impact by reducing the total number of cases. By reducing the number of pathogens that may be responsible for a particular clinical syndrome, vaccines can permit the use of narrower-spectrum antibiotics for empirical therapy. These effects may be amplified by herd immunity, extending protection to unvaccinated persons in the population. Because much selection for resistance is due to selection on bystander members of the normal flora, vaccination can reduce pressure for resistance even in pathogens not included in the vaccine. Some vaccines have had disproportionate effects on drug-resistant lineages within the target species, a benefit that could be more deliberately exploited in vaccine design. We describe the effects of current vaccines in controlling AMR, survey some vaccines in development with the potential to do so further, and discuss strategies to amplify these benefits. We conclude with a discussion of research and policy priorities to more fully enlist vaccines in the battle against AMR.
2015-06-25 | A Vaccine Approach for the Prevention of Infections by Multidrug-resistant Enterococcus faecium
The incidence of multidrug-resistant Enterococcus faecium hospital infections has been steadily increasing. With the goal of discovering new vaccine antigens, we systematically fractionated and purified four distinct surface carbohydrates from E. faecium endocarditis isolate Tx16, shown previously to be resistant to phagocytosis in the presence of human serum. The two most abundant polysaccharides consist of novel branched heteroglycan repeating units that include signature sugars altruronic acid and legionaminic acid, respectively. A minor high molecular weight polysaccharide component was recognized as the fructose homopolymer levan, and a glucosylated lipoteichoic acid (LTA) was identified in a micellar fraction. The polysaccharides were conjugated to the CRM197 carrier protein, and the resulting glycoconjugates were used to immunize rabbits. Rabbit immune sera were evaluated for their ability to kill Tx16 in opsonophagocytic assays and in a mouse passive protection infection model. Although antibodies raised against levan failed to mediate opsonophagocytic killing, the other glycoconjugates induced effective opsonic antibodies, with the altruronic acid-containing polysaccharide antisera showing the greatest opsonophagocytic assay activity. Antibodies directed against either novel heteroglycan or the LTA reduced bacterial load in mouse liver or kidney tissue. To assess antigen prevalence, we screened a diverse collection of blood isolates (n = 101) with antibodies to the polysaccharides. LTA was detected on the surface of 80% of the strains, and antigens recognized by antibodies to the two major heteroglycans were co-expressed on 63% of these clinical isolates. Collectively, these results represent the first steps toward identifying components of a glycoconjugate vaccine to prevent E. faecium infection.
2011-09-09 | Identification of SagA as a novel vaccine target for the prevention of Enterococcus faecium infections
Infections caused by multiresistant Gram-positive bacteria represent a major health burden in the community as well as in hospitalized patients. Enterococci, especially Enterococcus faecium, are well-known pathogens of hospitalized patients and are frequently linked with resistance against multiple antibiotics, which compromises effective therapy. Rabbit immune serum raised against heat-killed E. faecium E155, a HiRECC clone, was used in an opsonophagocytic assay, an inhibition assay and a mouse bacteraemia model to identify targets of opsonic and protective antibodies. Serum against whole heat-killed bacteria was opsonic and recognized a protein of about 72 kDa that was abundantly secreted. This protein, identified as SagA by LC-ES-MS/MS, was expressed in Escherichia coli and purified. Rabbit serum raised against the purified protein showed opsonic killing activity that was inhibited by almost 100 % using 100 µg purified protein ml −1 . In a mouse bacteraemia model, a statistically significant reduction of the colony counts in blood was shown with immune rabbit serum compared with preimmune serum using the homologous and a heterologous vancomycin-resistant enterococci (VRE) strain. These results indicate that SagA could be used as a promising vaccine target to treat and/or prevent VRE bacteraemia.
cell therapies
2025-11-21 | The gut microbiome as a major source of drug-resistant infections: emerging strategies to decolonize and target the gut reservoir.
Infections caused by antimicrobial-resistant bacteria represent a significant global health crisis that continues to worsen, creating an urgent need for alternative treatment and prevention strategies. A major source of drug-resistant bacteria is the human gut. The gut microbiota consists of bacteria that are frequently exposed to antibiotics, leading to selective pressure that promotes the development of resistant strains such as carbapenem-resistant Enterobacterales (CRE) and vancomycin-resistant enterococci (VRE). These drug-resistant bacteria can spread from the gut to other body sites, leading to hard-to-treat and potentially life-threatening infections such as bacteremia, surgical site infections, and urinary tract infections. Targeting the gut reservoir is essential in the fight against antimicrobial resistance. In this review, we focus on emerging non-antibiotic strategies aimed at eliminating drug resistant bacteria from the gut before they cause invasive infections, with particular emphasis on clinical evidence. Approaches discussed include fecal microbiota transplantation, bacteriophage therapy, antimicrobial peptides, probiotics, and dietary interventions. Optimizing these strategies, while continuing to explore newer approaches, will be essential to combat the growing threat of drug-resistant infections.
2025-02-22 | How can the gut microbiome be targeted to fight multidrug-resistant organisms?
The rise of antimicrobial resistance presents a challenge to public health, undermines the efficacy of antibiotics, and compromises the management of infectious diseases. Gut colonisation by multidrug-resistant organisms, such as multidrug-resistant Enterobacterales and vancomycin-resistant enterococci, is associated with increased morbidity and mortality rates, as well as health-care costs. Of late, the role of the gut microbiome in combating colonisation by multidrug-resistant organisms, which could precede invasive infection, has garnered interest. Innovative interventions, including faecal microbiota transplantation, probiotics, phage therapy, and bacterial consortia, represent potential preventive or therapeutic options to counteract colonisation by multidrug-resistant organisms. In this Personal View, we have synthesised the current findings on these interventions and elucidated their potential as solutions to the crisis of antimicrobial resistance.
2024-02-05 | Role of multidrug-resistant bacteria in weaning from invasive mechanical ventilation
Abstract Background Although multidrug-resistant bacteria (MDR) are common in patients undergoing prolonged weaning, there is little data on their impact on weaning and patient outcomes. Methods This is a retrospective analysis of consecutive patients who underwent prolonged weaning and were at a university weaning centre from January 2018 to December 2020. The influence of MDR colonisation and infection on weaning success (category 3a and 3b), successful prolonged weaning from invasive mechanical ventilation (IMV) with or without the need for non-invasive ventilation (NIV) compared with category 3c (weaning failure 3cI or death 3cII) was investigated. The pathogen groups considered were: multidrug-resistant gram-negative bacteria (MDRGN), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus spp. (VRE). Results A total of 206 patients were studied, of whom 91 (44.2%) showed evidence of MDR bacteria (32% VRE, 1.5% MRSA and 16% MDRGN), with 25 patients also meeting the criteria for MDR infection. 70.9% of the 206 patients were successfully weaned from IMV, 8.7% died. In 72.2% of cases, nosocomial pneumonia and other infections were the main cause of death. Patients with evidence of MDR (infection and colonisation) had a higher incidence of weaning failure than those without evidence of MDR (48% vs. 34.8% vs. 21.7%). In multivariate analyses, MDR infection (OR 4.9, p = 0.004) was an independent risk factor for weaning failure, along with male sex (OR 2.3, p = 0.025), Charlson Comorbidity Index (OR 1.2, p = 0.027), pH (OR 2.7, p < 0.001) and duration of IMV before admission (OR 1.01, p < 0.001). In addition, MDR infection was the only independent risk factor for death (category 3cII), (OR 6.66, p = 0.007). Conclusion Patients with MDR infection are significantly more likely to die during the weaning process. There is an urgent need to develop non-antibiotic approaches for the prevention and treatment of MDR infections as well as clinical research on antibiotic stewardship in prolonged weaning as well as in ICUs.
2022-05-04 | Synthetic Biology Tools for Engineering Microbial Cells to Fight Superbugs
With the increase in clinical cases of bacterial infections with multiple antibiotic resistance, the world has entered a health crisis. Overuse, inappropriate prescribing, and lack of innovation of antibiotics have contributed to the surge of microorganisms that can overcome traditional antimicrobial treatments. In 2017, the World Health Organization published a list of pathogenic bacteria, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii , Pseudomonas aeruginosa, and Escherichia coli (ESKAPE). These bacteria can adapt to multiple antibiotics and transfer their resistance to other organisms; therefore, studies to find new therapeutic strategies are needed. One of these strategies is synthetic biology geared toward developing new antimicrobial therapies. Synthetic biology is founded on a solid and well-established theoretical framework that provides tools for conceptualizing, designing, and constructing synthetic biological systems. Recent developments in synthetic biology provide tools for engineering synthetic control systems in microbial cells. Applying protein engineering, DNA synthesis, and in silico design allows building metabolic pathways and biological circuits to control cellular behavior. Thus, synthetic biology advances have permitted the construction of communication systems between microorganisms where exogenous molecules can control specific population behaviors, induce intracellular signaling, and establish co-dependent networks of microorganisms.
2021-10-13 | Faecal microbiota replacement to eradicate antimicrobial resistant bacteria in the intestinal tract – a systematic review
Antimicrobial resistance is a rising threat to global health and is associated with increased mortality. Intestinal colonisation with multidrug-resistant organisms (MDRO) can precede invasive infection and facilitates spread within communities and hospitals. Novel decolonisation strategies, such as faecal microbiota transplantation (FMT), are being explored. The purpose of this review is to provide an update on how the field of FMT for MDRO decolonisation has developed during the past year and to assess the efficacy of FMT for intestinal MDRO decolonisation.Since 2020, seven highly heterogenous, small, nonrandomised cohort studies and five case reports have been published. In line with previous literature, decolonisation rates ranged from 20 to 90% between studies and were slightly higher for carbapenem-resistant Enterobacteriaceae than vancomycin-resistant Enterococcus. Despite moderate decolonisation rates in two studies, a reduction in MDRO bloodstream and urinary tract infections was observed.Although a number of smaller cohort studies show some effect of FMT for MDRO decolonisation, questions remain regarding the true efficacy of FMT (taking spontaneous decolonisation into account), the optimal route of administration, the role of antibiotics pre and post-FMT and the efficacy in different patient populations. The observed decrease in MDRO infections post-FMT warrants further research.
other
2024-03-18 | Analytical and Clinical Validation of Direct Detection of Antimicrobial Resistance Markers by Plasma Microbial Cell-free DNA Sequencing
ABSTRACT Sequencing of plasma microbial cell-free DNA (mcfDNA) has gained increased acceptance as a valuable adjunct to standard-of-care testing for diagnosis of infections throughout the body. Here we report the analytical and clinical validation of a novel application of mcfDNA sequencing, the non-invasive detection of seven common antimicrobial resistance (AMR) genetic markers in 18 important pathogens with potential to harbor these markers. The AMR markers include SCC mec , mecA and mecC for methicillin, vanA and vanB for vancomycin, bla CTX-M for oxyimino-cephalosporin and aztreonam, and bla KPC for carbapenem resistance. The AMR markers are computationally linked to the pathogens detected, using a statistical model based on observed AMR gene and pathogen abundances. Analytical validation showed high reproducibility (100%), inclusivity (54 to100%), and exclusivity (100%), with limits of detection ranging from 425 to 6,107 pathogen mcfDNA molecules/μL for the different markers. Clinical accuracy was assessed with 115 unique plasma samples from patients at 7 study sites with concordant culture results for 12/18 (66.7%) target bacteria from a variety of specimen types and correlated with available phenotypic antimicrobial susceptibility test results and genotypic results when available. The positive percent agreement (PPA), negative percent agreement (NPA), overall percent agreement (OPA), and diagnostic yield (DY) were estimated for each AMR marker. The results for the combination of SCC mec and mecA for staphylococci were PPA 19/20 (95.0%), NPA 21/22 (95.4%), OPA 40/42 (95.2%), DY 42/60 (70.0%); vanA for enterococci were PPA 3/3 (100%), NPA 2/2 (100%), OPA5/5 (100%), DY 5/6 (83.3%); bla CTX-M for gram-negative bacilli were PPA 5/6 (83.3%), NPA 29/29 (100%), OPA34/35 (97.1%), DY 35/49 (71.4%); and bla KPC for gram-negative bacilli were PPA 0/2 (0%), NPA: 23/23 (100%), OPA23/25 (92.3%), DY 25/44 (56.8%). The addition of AMR capability to plasma mcfDNA sequencing should provide clinicians with an effective new culture-independent tool for optimization of therapy.
2018-05-01 | Bacterial Adaptation to Antibiotics through Regulatory RNAs
The extensive use of antibiotics has resulted in a situation where multidrug-resistant pathogens have become a severe menace to human health worldwide. A deeper understanding of the principles used by pathogens to adapt to, respond to, and resist antibiotics would pave the road to the discovery of drugs with novel mechanisms. For bacteria, antibiotics represent clinically relevant stresses that induce protective responses. The recent implication of regulatory RNAs (small RNAs [sRNAs]) in antibiotic response and resistance in several bacterial pathogens suggests that they should be considered innovative drug targets. This minireview discusses sRNA-mediated mechanisms exploited by bacterial pathogens to fight against antibiotics. A critical discussion of the newest findings in the field is provided, with emphasis on the implication of sRNAs in major mechanisms leading to antibiotic resistance, including drug uptake, active drug efflux, drug target modifications, biofilms, cell walls, and lipopolysaccharide (LPS) biosynthesis. Of interest is the lack of knowledge about sRNAs implicated in Gram-positive compared to Gram-negative bacterial resistance.
2013-03-01 | Antimicrobial Aptamers for Detection and Inhibition of Microbial Pathogen Growth
Discovery of alternative sources of antimicrobial agents are essential in the ongoing battle against microbial pathogens. Legislative and scientific challenges considerably hinder the discovery and use of new antimicrobial drugs, and new approaches are in urgent demand. On the other hand, rapid, specific and sensitive detection of airborne pathogens is becoming increasingly critical for public health. In this respect affinity oligonucleotides, aptamers, provide unique opportunities for the development of nanotechnological solutions for such medical applications. In recent years, aptamers specifically recognizing microbial cells and viruses showed great potential in a range of analytical and therapeutic applications. This article describes the significant advances in the development of aptamers targeting specific pathogens. Therapeutic application of aptamers as neutralizing agents demonstrates great potential as a future source of antimicrobial agent.
2010-06-01 | Antisense Antibiotics: A Brief Review of Novel Target Discovery and Delivery
The nightmare of multi-drug resistant bacteria will still haunt if no panacea is ever found. Efforts on seeking desirable natural products with bactericidal property and screening chemically modified derivatives of traditional antibiotics have lagged behind the emergence of new multi-drug resistant bacteria. The concept of using antisense antibiotics, now as revolutionary as is on threshold has experienced ups and downs in the past decade. In the past five years, however, significant technology advances in the fields of microbial genomics, structural modification of oligonucleotides and efficient delivery system have led to fundamental progress in the research and in vivo application of this paradigm. The wealthy information provided in the microbial genomics era has allowed the identification and/or validation of a number of essential genes that may serve as possible targets for antisense inhibition; antisense oligodeoxynucleotides (ODNs) based on the 3rd generation of modified structures, e.g., peptide nucleic acids (PNAs) and phosphorodiamidate morpholino oligomers (PMOs) have shown great potency in gene expression inhibition in a sequence-specific and dosedependent manner at low micromolar concentrations; and cell penetrating peptide mediated delivery system has enabled the effective display of intracellular antisense inhibition of targeted genes both in vitro and in vivo. The new methods show promise in the discovery of novel gene-specific antisense antibiotics that will be useful in the future battle against drug-resistant bacterial infections. This review describes this promising paradigm, the targets that have been identified and the recent technologies on which it is delivered. Keywords: Antisense oligonucleotides, antisense antibiotics, antibiotic resistance, oligodeoxynucleotides, (ODNs), morpholino oligomers (PMOs), peptide nucleic acids, (PNAs), phosphorodiamidate morpholino oligomers, (PMOs), Staphylococcus aureus, MRSA, Enterococci, VRE, Mycobacterium tuberculosis, Escherichia coli, Klebsiella pneumonia, Pseudomonades, Acinetobacter, pathogenesis, DNA replication, RNA, PS-ODNs, LNAs, Phos phorothioa te DNA, 2'-O-Methox yethyl RNA, (2'-MOE), 2'-O-methyl RNA, Phosphorodiamidate Morpholino, Thiophosphoramidate, Locked Nucleic Acid, Bicyclic Nucleic Acid, β-lactamase, Enterococcus faecalis, Campylobacter jejun, Bacillus anthracis, Mycobacterium smegmatis, Mycobacterium avium, Entamoeba histolytica, Streptococcus mutans, Burkholderia cepacia, Salmonella enterica serovar Typhimurium, gene therapy, gram-negative bacteria, Antibacterial Therapy, Cell penetrating peptide, Pseudomonas aeruginosa, Bacillus subtilis, Corynebacterium efficiens
small molecules
2026-08-01 | Characterization of vancomycin-resistant Enterococcus faecium in children admitted to a pediatric oncology hospital in the city of São Paulo Brazil
Abstract Background Vancomycin-resistant Enterococcus (VRE) is an important microorganism in nosocomial infections in pediatric oncology patients. Immunosuppression, prolonged use of antimicrobials (particularly cephalosporins and vancomycin) and invasive procedures are the main risk factors for acquiring infection by this agent. Furthermore, studies have shown that exposure of a patient bed previously occupied by a VRE carrier can be considered a risk factor for acquiring new in-patient infections. The aim of this study was to evaluate the colonization of Enterococcus faecium vancomycin- resistant (EfmVRE) and further infection in children admitted to a reference pediatric oncology hospital. Methods Retrospective cohort study conducted at a reference pediatric oncology hospital in Sao Paulo, Brazil and the Federal University of Sao Paulo. Inclusion criteria: samples from patients who were followed up during the period from January to December 2009 and who presented a positive surveillance culture for EfmVRE with a later positive clinical culture for the same agent were included in the study. We analyzed 10 samples of EfmVRE in 2009, two samples from each patient: one representative of colonization site and another of the site of infection using the analysis of the profile generated after chromosomal restriction digestion (SmaI) of the samples by PFGE, then analyzed byBioNumerics ® software, according to the microrestriction pattern obtained. Results We observed that five pediatric patients were colonized (3 rectal swabs, 1 IV catheter and 1 tracheal aspirate) by EfmVRE, and subsequently developed bloodstream infection by the same agent. We also observed a genetic similarity among representative samples of infection and colonization, from the same patient, except the patient 2. Genetic clonal profiles were observed (100% similarity) between samples isolated from patient 1 and patient 5. 95.7% similarity was observed in samples from patient 3 and 90.9% in samples of patient 4. An important fact is that patients 1, 2 and 5 were admitted to the pediatric ICU within two months period, this might explain the genetic similarity observed among the respective isolates. The finding of clonal samples as demonstrated in our study suggests that patients presenting EfmVRE colonization prior to associated risk factors developed infection due to these microorganisms. Conclusions It was also observed that there was a high degree of similarity (> 80%) among isolates from different patients and from different hospitals belonging to the same hospital complex. Earlier detection of EfmVRE colonizing patients could prevent its spreading in the hospital. In fact, two vulnerable patients died, one treated for a bloodstream infection with linezolid. Our findings point to the need of studies for EfmVR decolonization in susceptible patient to prevent further infection.
2026-07-13 | Long-Acting Lipoglycopeptide Treatment of Invasive Gram-Positive Infections.
Gram-positive infections continue to pose a therapeutic challenge owing to their invasive nature (e.g., Staphylococcus aureus and Streptococcus pyogenes) and eradication difficulties (e.g., methicillin-resistant Staphylococcus aureus [MRSA] and vancomycin-resistant enterococci [VRE]). Long-acting lipoglycopeptides (laLGPs) present an effective and conveniently dosed option for the treatment of most invasive Gram-positive pathogens. Improved compliance monitoring associated with their infrequent intravenous dosing, that is not available to such degree with more frequently dosed antimicrobials outside of inpatient settings, is another benefit of laLGPs over more frequently dosed antimicrobials. In this article, we provide a narrative review, including the pharmacological characteristics of dalbavancin (DAL) and oritavancin (ORI), the only currently available laLGPs, as well as their approved and "off-label" use reported in the literature to date. We discuss their respective mechanism of action, caveats in compartments where they do not achieve sufficient concentrations (i.e., central nervous system [CNS]; potentially pneumonias with ORI), as well as their reported efficacy in individual organ systems as reported in literature. Lastly, we summarize insights about laLGP use in special populations and discuss the benefits of therapeutic drug monitoring of these agents, mainly in conditions requiring prolonged therapy (e.g., hardware-associated orthopedic infections).
2026-01-01 | Clinical, genomic, and functional characterization of vancomycin-resistant Enterococci from immunocompromised patients: insights into epithelial dysfunction and bloodstream infections.
Vancomycin-resistant Enterococcus faecium and Enterococcus faecalis (VRE) are increasingly recognized as major opportunistic pathogens in immunocompromised patients, where they may cause bloodstream infections (BSIs). The present study aimed to characterize a cohort of immunocompromised patients colonized or infected with VRE, performing genomic analysis of these isolates. Additionally, we investigated the impact of bacterial culture supernatants on Caco-2 epithelial cells, focusing on adhesion and cytotoxicity to elucidate mechanisms related to epithelial dysfunction and bacterial translocation. We conducted a retrospective study including 46 VRE from two Italian hospitals. Clinical and epidemiological data were collected, and isolates were characterized by antimicrobial susceptibility testing and whole-genome sequencing. Four representative isolates (E. faecium ST80, E. faecium ST117, E. faecalis ST28, and E. faecalis ST179) and two reference strains (ATCC 29212™ and ATCC 51299™) were selected for in vitro analyses. Adhesion to Caco-2 monolayers was quantified, while cytotoxicity was assessed using MTT assays with bacterial cell-free supernatants (CS). Hydrogen peroxide (H2O2) production was measured using the Amplex® Red Hydrogen Peroxide/Peroxidase Assay Kit. The majority of isolates were E. faecium (78.3%), predominantly ST80 and ST117, possessed multiple resistance determinants. E. faecalis isolates displayed greater sequence type diversity with a ST28 predominance, carrying virulence genes as ebp, gelE, and elrA. In vitro, bloodstream-derived isolates (E. faecium 51, E. faecalis 52) and reference strain ATCC 29212™ adhered more strongly to Caco-2 cells than other isolates. CS from invasive isolates and ATCC 51299™ significantly reduced epithelial cell viability at 24 h (p < 0.01). In these isolates, H2O2 higher quantification was documented in a cellular model. Our findings highlighted the convergence of antimicrobial resistance and virulence traits in VRE, alongside functional evidence of strain-dependent adhesion and secretion of cytotoxic metabolites. Elevated H2O2 production provides a possible path between enterococcal secretomes and epithelial injury, suggesting oxidative stress as a contributor to epithelial dysfunction and potential translocation. These insights expand current understanding of VRE pathogenesis and point to novel therapeutic approaches aimed at preserving epithelial integrity and mitigating oxidative damage in high-risk patients.
2025-10-02 | Impact of the COVID-19 pandemic on vancomycin-resistant Enterococcus bloodstream infections: a 6-year study in Western Greece
Background Antimicrobial resistance is a critical and growing global health concern. While drug-resistant Gram-negative bacilli pose a significant threat, multidrug-resistant Gram-positive bacteria—such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and β-lactamase-resistant Streptococcus pneumoniae —also present serious clinical challenges. Aim This study provides an epidemiological analysis of resistant Gram-positive bacteria, focusing on VRE, at a tertiary university hospital in Western Greece from 2018 to 2023. Results A total of 276 blood cultures with vancomycin-resistant Enterococcus spp. were recorded. A significant increase in VRE prevalence was observed in intensive care units (ICUs), with cases rising from 4 in 2020 to 36 in 2021. A broader increase across medical and surgical wards was noted in 2022–2023. Linezolid resistance remained low throughout the study period. Mortality data revealed a marked increase in deaths after 2020 compared to 2018–2019, coinciding with the rise in VRE-related bloodstream infections. The Coronavirus Disease 2019 (COVID-19) pandemic was associated with higher VRE rates in ICU patients, likely due to prolonged hospitalizations, increased use of invasive devices, and broad-spectrum antibiotic use. Resistance rates to both linezolid and tigecycline remained low, while daptomycin resistance showed an increasing trend the same period. Conclusion The number of VRE increased over the study period. Linezolid and tigecycline remained largely effective, but emerging resistance patterns—particularly to daptomycin—underscore the urgent need for strengthened antimicrobial stewardship and the development of novel therapeutic options to address rising resistance among Gram-positive pathogens.
2025-09-21 | A risk-based assessment of Enterococcal Bloodstream infection: Suggesting considerations in empirical therapy strategies in a tertiary care hospital.
Enterococcal bloodstream infections (E-BSIs) pose a significant challenge due to their unique intrinsic and increasing resistance. Empirical treatment guidelines are often ineffective in E-BSI, as Antibiotic policies mainly address Gram-negative bacilli and MRSA for Hospital-acquired infection (HAI) in India. The study was designed to investigate the risk factors, infection source, species profile, antimicrobial susceptibility and clinical outcomes in diagnosed E-BSI patients at a tertiary care centre in India. From the blood culture samples from August 2022 to July 2023, 52 non-duplicate blood culture isolates of Enterococcus species were identified with categorisation of vancomycin resistance genes, and the patients were followed up for risk factors, probable sources, and ongoing therapies, with a switch to definitive therapy for the outcome. Of 52 confirmed E-BSI cases, the species distribution was as follows: E. faecium (61.5 %), E. faecalis (26.92 %), E. gallinarum (9.61 %), and E. durans (1.92 %). Antimicrobial resistance was significantly higher in E. faecium. Nine isolates (17.3 %) were vancomycin-resistant enterococci (VRE), with diverse outcomes. HAI comprised 44.23 % of cases. The overall mortality rate was 26.9 % and ICU patients had significantly higher mortality, with significant risk factors being invasive medical devices (59.6 %), followed by bedridden status (23 %) and immunosuppression (9.61 %). Significant risk factors included the presence of invasive medical devices (59.6 %), followed by a bedridden status (23.0 %) and immunosuppression (9.6 %). Patients with early empirical therapy that has enterococcal coverage showed a protective effect on survival. However, switching over to definitive therapy alone could not significantly reduce mortality. This study underscores the importance of early empirical therapy with enterococcal coverage in high-risk patients. Timely initiation of empirical coverage appears more crucial than later definitive therapy adjustments in improving survival. Invasive device use remains a significant risk factor, reinforcing the need for stringent infection control to prevent HAI, including E-BSI.
proteins
2024-04-09 | A Comprehensive Review of Recent Research into the Effects of Antimicrobial Peptides on Biofilms—January 2020 to September 2023
Microbial biofilm formation creates a persistent and resistant environment in which microorganisms can survive, contributing to antibiotic resistance and chronic inflammatory diseases. Increasingly, biofilms are caused by multi-drug resistant microorganisms, which, coupled with a diminishing supply of effective antibiotics, is driving the search for new antibiotic therapies. In this respect, antimicrobial peptides (AMPs) are short, hydrophobic, and amphipathic peptides that show activity against multidrug-resistant bacteria and biofilm formation. They also possess broad-spectrum activity and diverse mechanisms of action. In this comprehensive review, 150 publications (from January 2020 to September 2023) were collected and categorized using the search terms ‘polypeptide antibiotic agent’, ‘antimicrobial peptide’, and ‘biofilm’. During this period, a wide range of natural and synthetic AMPs were studied, of which LL-37, polymyxin B, GH12, and Nisin were the most frequently cited. Furthermore, although many microbes were studied, Staphylococcus aureus and Pseudomonas aeruginosa were the most popular. Publications also considered AMP combinations and the potential role of AMP delivery systems in increasing the efficacy of AMPs, including nanoparticle delivery. Relatively few publications focused on AMP resistance. This comprehensive review informs and guides researchers about the latest developments in AMP research, presenting promising evidence of the role of AMPs as effective antimicrobial agents.
2024-03-08 | LL-37: Structures, Antimicrobial Activity, and Influence on Amyloid-Related Diseases
Antimicrobial peptides (AMPs), as well as host defense peptides (HDPs), constitute the first line of defense as part of the innate immune system. Humans are known to express antimicrobial precursor proteins, which are further processed to generate AMPs, including several types of α/β defensins, histatins, and cathelicidin-derived AMPs like LL37. The broad-spectrum activity of AMPs is crucial to defend against infections caused by pathogenic bacteria, viruses, fungi, and parasites. The emergence of multi-drug resistant pathogenic bacteria is of global concern for public health. The prospects of targeting antibiotic-resistant strains of bacteria with AMPs are of high significance for developing new generations of antimicrobial agents. The 37-residue long LL37, the only cathelicidin family of AMP in humans, has been the major focus for the past few decades of research. The host defense activity of LL37 is likely underscored by its expression throughout the body, spanning from the epithelial cells of various organs—testis, skin, respiratory tract, and gastrointestinal tract—to immune cells. Remarkably, apart from canonical direct killing of pathogenic organisms, LL37 exerts several other host defense activities, including inflammatory response modulation, chemo-attraction, and wound healing and closure at the infected sites. In addition, LL37 and its derived peptides are bestowed with anti-cancer and anti-amyloidogenic properties. In this review article, we aim to develop integrative, mechanistic insight into LL37 and its derived peptides, based on the known biophysical, structural, and functional studies in recent years. We believe that this review will pave the way for future research on the structures, biochemical and biophysical properties, and design of novel LL37-based molecules.
2024-03-01 | Exploring the feasibility of bacteriocins EntK1 and EntEJ97s in treatment of systemic VRE infections in mice
Abstract Aims Enterocins K1 and EJ97 have specific antimicrobial activity against Enterococcus faecium and Enterococcus faecalis, respectively. The aim of this study was to investigate the utility of these enterocins for in vivo treatment of systemic enterococcal infections. Methods and results The antimicrobial effect in blood was analysed and compared against the effect in saline. Colony forming unit counts revealed that the enterocins killed all the bacteria within 1 hour. Additionally, the bactericidal effect against E. faecalis was more rapid in blood, indicating a possible synergy between EntEJ97 and blood. Importantly, no enterocin resistant mutants emerged in these experiments. Injecting the enterocins intraperitoneally in an in vivo mouse model and using fluorescence and minimum inhibitory concentration determination to estimate concentrations of the peptides in plasma, indicate that the enterocins exist in circulation in therapeutic concentrations. Alanine aminotransferase detection, and haemolysis analysis indicates that there is no detectable liver damage or haemolytic effect after injection. Conclusions The study revealed that EntK1 and EntEJ97 are able to kill all bacteria ex vivo in the presence of blood. In vivo experiments determine that the enterocins exist in circulation in therapeutic concentrations without causing liver damage or haemolysis. Future experiments should test these peptides for treatment of infection in a relevant in vivo model.
2024-02-24 | Molecular Aspects of the Functioning of Pathogenic Bacteria Biofilm Based on Quorum Sensing (QS) Signal-Response System and Innovative Non-Antibiotic Strategies for Their Elimination
One of the key mechanisms enabling bacterial cells to create biofilms and regulate crucial life functions in a global and highly synchronized way is a bacterial communication system called quorum sensing (QS). QS is a bacterial cell-to-cell communication process that depends on the bacterial population density and is mediated by small signalling molecules called autoinducers (AIs). In bacteria, QS controls the biofilm formation through the global regulation of gene expression involved in the extracellular polymeric matrix (EPS) synthesis, virulence factor production, stress tolerance and metabolic adaptation. Forming biofilm is one of the crucial mechanisms of bacterial antimicrobial resistance (AMR). A common feature of human pathogens is the ability to form biofilm, which poses a serious medical issue due to their high susceptibility to traditional antibiotics. Because QS is associated with virulence and biofilm formation, there is a belief that inhibition of QS activity called quorum quenching (QQ) may provide alternative therapeutic methods for treating microbial infections. This review summarises recent progress in biofilm research, focusing on the mechanisms by which biofilms, especially those formed by pathogenic bacteria, become resistant to antibiotic treatment. Subsequently, a potential alternative approach to QS inhibition highlighting innovative non-antibiotic strategies to control AMR and biofilm formation of pathogenic bacteria has been discussed.
2024-02-23 | Study of an Enterococcus faecium strain isolated from an artisanal Mexican cheese, whole-genome sequencing, comparative genomics, and bacteriocin expression
Abstract Enterococci are ubiquitous microorganisms in almost all environments, from the soil we step on to the food we eat. They are frequently found in naturally fermented foods, contributing to ripening through protein, lipid, and sugar metabolism. On the other hand, these organisms are also leading the current antibiotic resistance crisis. In this study, we performed whole-genome sequencing and comparative genomics of an Enterococcus faecium strain isolated from an artisanal Mexican Cotija cheese, namely QD-2. We found clear genomic differences between commensal and pathogenic strains, particularly in their carbohydrate metabolic pathways, resistance to vancomycin and other antibiotics, bacteriocin production, and bacteriophage and CRISPR content. Furthermore, a bacteriocin transcription analysis performed by RT-qPCR revealed that, at the end of the log phase, besides enterocins A and X, two putative bacteriocins not reported previously are also transcribed as a bicistronic operon in E. faecium QD-2, and are expressed 1.5 times higher than enterocin A when cultured in MRS broth.
vaccines
2022-05-27 | Designing a novel multi-epitope vaccine to evoke a robust immune response against pathogenic multidrug-resistant Enterococcus faecium bacterium
Enterococcus faecium is an emerging ESKAPE bacterium that is capable of causing severe public health complications in humans. There are currently no licensed treatments or vaccinations to combat the deadly pathogen. We aimed to design a potent and novel prophylactic chimeric vaccine against E. faecium through an immunoinformatics approach The antigenic Penicillin-binding protein 5 (PBP 5) protein was selected to identify B and T cell epitopes, followed by conservancy analysis, population coverage, physiochemical assessment, secondary and tertiary structural analysis. Using various immunoinformatics methods and tools, two linear B-cell epitopes, five CTL epitopes, and two HTL epitopes were finally selected for vaccine development. The constructed vaccine was determined to be highly immunogenic, cytokine-producing, antigenic, non-toxic, non-allergenic, and stable, as well as potentially effective against E. faecium. In addition, disulfide engineering, codon adaptation, and in silico cloning, were used to improve stability and expression efficiency in the host E. coli. Molecular docking and molecular dynamics simulations indicated that the structure of the vaccine is stable and has a high affinity for the TLR4 receptor. The immune simulation results revealed that both B and T cells had an increased response to the vaccination component. Conclusively, the in-depth in silico analysis suggests, the proposed vaccine to elicit a robust immune response against E. faecium infection and hence a promising target for further experimental trials.
2017-12-20 | Physiology and Pathology of Multidrug-Resistant Bacteria: Antibodies- and Vaccines-Based Pathogen-Specific Targeting
Multidrug-resistant bacteria (MDR) are increasing rapidly and posing a global threat to mankind. Alternative strategies other than antibiotics have to be explored urgently. In this chapter, we review the current status of nonantibiotics strategies including antibody-based therapy and vaccine development for targeting Gram-positive strains (methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium) and MDR Gram-negative strains (Acinetobacter baumannii and Pseudomonas aeruginosa). Biologics-based clinical progress against these bacterial infections is updated.
2016-07-06 | How Can Vaccines Contribute to Solving the Antimicrobial Resistance Problem?
There is a growing appreciation for the role of vaccines in confronting the problem of antimicrobial resistance (AMR). Vaccines can reduce the prevalence of resistance by reducing the need for antimicrobial use and can reduce its impact by reducing the total number of cases. By reducing the number of pathogens that may be responsible for a particular clinical syndrome, vaccines can permit the use of narrower-spectrum antibiotics for empirical therapy. These effects may be amplified by herd immunity, extending protection to unvaccinated persons in the population. Because much selection for resistance is due to selection on bystander members of the normal flora, vaccination can reduce pressure for resistance even in pathogens not included in the vaccine. Some vaccines have had disproportionate effects on drug-resistant lineages within the target species, a benefit that could be more deliberately exploited in vaccine design. We describe the effects of current vaccines in controlling AMR, survey some vaccines in development with the potential to do so further, and discuss strategies to amplify these benefits. We conclude with a discussion of research and policy priorities to more fully enlist vaccines in the battle against AMR.
2015-06-25 | A Vaccine Approach for the Prevention of Infections by Multidrug-resistant Enterococcus faecium
The incidence of multidrug-resistant Enterococcus faecium hospital infections has been steadily increasing. With the goal of discovering new vaccine antigens, we systematically fractionated and purified four distinct surface carbohydrates from E. faecium endocarditis isolate Tx16, shown previously to be resistant to phagocytosis in the presence of human serum. The two most abundant polysaccharides consist of novel branched heteroglycan repeating units that include signature sugars altruronic acid and legionaminic acid, respectively. A minor high molecular weight polysaccharide component was recognized as the fructose homopolymer levan, and a glucosylated lipoteichoic acid (LTA) was identified in a micellar fraction. The polysaccharides were conjugated to the CRM197 carrier protein, and the resulting glycoconjugates were used to immunize rabbits. Rabbit immune sera were evaluated for their ability to kill Tx16 in opsonophagocytic assays and in a mouse passive protection infection model. Although antibodies raised against levan failed to mediate opsonophagocytic killing, the other glycoconjugates induced effective opsonic antibodies, with the altruronic acid-containing polysaccharide antisera showing the greatest opsonophagocytic assay activity. Antibodies directed against either novel heteroglycan or the LTA reduced bacterial load in mouse liver or kidney tissue. To assess antigen prevalence, we screened a diverse collection of blood isolates (n = 101) with antibodies to the polysaccharides. LTA was detected on the surface of 80% of the strains, and antigens recognized by antibodies to the two major heteroglycans were co-expressed on 63% of these clinical isolates. Collectively, these results represent the first steps toward identifying components of a glycoconjugate vaccine to prevent E. faecium infection.
2011-09-09 | Identification of SagA as a novel vaccine target for the prevention of Enterococcus faecium infections
Infections caused by multiresistant Gram-positive bacteria represent a major health burden in the community as well as in hospitalized patients. Enterococci, especially Enterococcus faecium, are well-known pathogens of hospitalized patients and are frequently linked with resistance against multiple antibiotics, which compromises effective therapy. Rabbit immune serum raised against heat-killed E. faecium E155, a HiRECC clone, was used in an opsonophagocytic assay, an inhibition assay and a mouse bacteraemia model to identify targets of opsonic and protective antibodies. Serum against whole heat-killed bacteria was opsonic and recognized a protein of about 72 kDa that was abundantly secreted. This protein, identified as SagA by LC-ES-MS/MS, was expressed in Escherichia coli and purified. Rabbit serum raised against the purified protein showed opsonic killing activity that was inhibited by almost 100 % using 100 µg purified protein ml −1 . In a mouse bacteraemia model, a statistically significant reduction of the colony counts in blood was shown with immune rabbit serum compared with preimmune serum using the homologous and a heterologous vancomycin-resistant enterococci (VRE) strain. These results indicate that SagA could be used as a promising vaccine target to treat and/or prevent VRE bacteraemia.
cell therapies
2025-11-21 | The gut microbiome as a major source of drug-resistant infections: emerging strategies to decolonize and target the gut reservoir.
Infections caused by antimicrobial-resistant bacteria represent a significant global health crisis that continues to worsen, creating an urgent need for alternative treatment and prevention strategies. A major source of drug-resistant bacteria is the human gut. The gut microbiota consists of bacteria that are frequently exposed to antibiotics, leading to selective pressure that promotes the development of resistant strains such as carbapenem-resistant Enterobacterales (CRE) and vancomycin-resistant enterococci (VRE). These drug-resistant bacteria can spread from the gut to other body sites, leading to hard-to-treat and potentially life-threatening infections such as bacteremia, surgical site infections, and urinary tract infections. Targeting the gut reservoir is essential in the fight against antimicrobial resistance. In this review, we focus on emerging non-antibiotic strategies aimed at eliminating drug resistant bacteria from the gut before they cause invasive infections, with particular emphasis on clinical evidence. Approaches discussed include fecal microbiota transplantation, bacteriophage therapy, antimicrobial peptides, probiotics, and dietary interventions. Optimizing these strategies, while continuing to explore newer approaches, will be essential to combat the growing threat of drug-resistant infections.
2025-02-22 | How can the gut microbiome be targeted to fight multidrug-resistant organisms?
The rise of antimicrobial resistance presents a challenge to public health, undermines the efficacy of antibiotics, and compromises the management of infectious diseases. Gut colonisation by multidrug-resistant organisms, such as multidrug-resistant Enterobacterales and vancomycin-resistant enterococci, is associated with increased morbidity and mortality rates, as well as health-care costs. Of late, the role of the gut microbiome in combating colonisation by multidrug-resistant organisms, which could precede invasive infection, has garnered interest. Innovative interventions, including faecal microbiota transplantation, probiotics, phage therapy, and bacterial consortia, represent potential preventive or therapeutic options to counteract colonisation by multidrug-resistant organisms. In this Personal View, we have synthesised the current findings on these interventions and elucidated their potential as solutions to the crisis of antimicrobial resistance.
2024-02-05 | Role of multidrug-resistant bacteria in weaning from invasive mechanical ventilation
Abstract Background Although multidrug-resistant bacteria (MDR) are common in patients undergoing prolonged weaning, there is little data on their impact on weaning and patient outcomes. Methods This is a retrospective analysis of consecutive patients who underwent prolonged weaning and were at a university weaning centre from January 2018 to December 2020. The influence of MDR colonisation and infection on weaning success (category 3a and 3b), successful prolonged weaning from invasive mechanical ventilation (IMV) with or without the need for non-invasive ventilation (NIV) compared with category 3c (weaning failure 3cI or death 3cII) was investigated. The pathogen groups considered were: multidrug-resistant gram-negative bacteria (MDRGN), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus spp. (VRE). Results A total of 206 patients were studied, of whom 91 (44.2%) showed evidence of MDR bacteria (32% VRE, 1.5% MRSA and 16% MDRGN), with 25 patients also meeting the criteria for MDR infection. 70.9% of the 206 patients were successfully weaned from IMV, 8.7% died. In 72.2% of cases, nosocomial pneumonia and other infections were the main cause of death. Patients with evidence of MDR (infection and colonisation) had a higher incidence of weaning failure than those without evidence of MDR (48% vs. 34.8% vs. 21.7%). In multivariate analyses, MDR infection (OR 4.9, p = 0.004) was an independent risk factor for weaning failure, along with male sex (OR 2.3, p = 0.025), Charlson Comorbidity Index (OR 1.2, p = 0.027), pH (OR 2.7, p < 0.001) and duration of IMV before admission (OR 1.01, p < 0.001). In addition, MDR infection was the only independent risk factor for death (category 3cII), (OR 6.66, p = 0.007). Conclusion Patients with MDR infection are significantly more likely to die during the weaning process. There is an urgent need to develop non-antibiotic approaches for the prevention and treatment of MDR infections as well as clinical research on antibiotic stewardship in prolonged weaning as well as in ICUs.
2022-05-04 | Synthetic Biology Tools for Engineering Microbial Cells to Fight Superbugs
With the increase in clinical cases of bacterial infections with multiple antibiotic resistance, the world has entered a health crisis. Overuse, inappropriate prescribing, and lack of innovation of antibiotics have contributed to the surge of microorganisms that can overcome traditional antimicrobial treatments. In 2017, the World Health Organization published a list of pathogenic bacteria, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii , Pseudomonas aeruginosa, and Escherichia coli (ESKAPE). These bacteria can adapt to multiple antibiotics and transfer their resistance to other organisms; therefore, studies to find new therapeutic strategies are needed. One of these strategies is synthetic biology geared toward developing new antimicrobial therapies. Synthetic biology is founded on a solid and well-established theoretical framework that provides tools for conceptualizing, designing, and constructing synthetic biological systems. Recent developments in synthetic biology provide tools for engineering synthetic control systems in microbial cells. Applying protein engineering, DNA synthesis, and in silico design allows building metabolic pathways and biological circuits to control cellular behavior. Thus, synthetic biology advances have permitted the construction of communication systems between microorganisms where exogenous molecules can control specific population behaviors, induce intracellular signaling, and establish co-dependent networks of microorganisms.
2021-10-13 | Faecal microbiota replacement to eradicate antimicrobial resistant bacteria in the intestinal tract – a systematic review
Antimicrobial resistance is a rising threat to global health and is associated with increased mortality. Intestinal colonisation with multidrug-resistant organisms (MDRO) can precede invasive infection and facilitates spread within communities and hospitals. Novel decolonisation strategies, such as faecal microbiota transplantation (FMT), are being explored. The purpose of this review is to provide an update on how the field of FMT for MDRO decolonisation has developed during the past year and to assess the efficacy of FMT for intestinal MDRO decolonisation.Since 2020, seven highly heterogenous, small, nonrandomised cohort studies and five case reports have been published. In line with previous literature, decolonisation rates ranged from 20 to 90% between studies and were slightly higher for carbapenem-resistant Enterobacteriaceae than vancomycin-resistant Enterococcus. Despite moderate decolonisation rates in two studies, a reduction in MDRO bloodstream and urinary tract infections was observed.Although a number of smaller cohort studies show some effect of FMT for MDRO decolonisation, questions remain regarding the true efficacy of FMT (taking spontaneous decolonisation into account), the optimal route of administration, the role of antibiotics pre and post-FMT and the efficacy in different patient populations. The observed decrease in MDRO infections post-FMT warrants further research.
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2024-03-18 | Analytical and Clinical Validation of Direct Detection of Antimicrobial Resistance Markers by Plasma Microbial Cell-free DNA Sequencing
ABSTRACT Sequencing of plasma microbial cell-free DNA (mcfDNA) has gained increased acceptance as a valuable adjunct to standard-of-care testing for diagnosis of infections throughout the body. Here we report the analytical and clinical validation of a novel application of mcfDNA sequencing, the non-invasive detection of seven common antimicrobial resistance (AMR) genetic markers in 18 important pathogens with potential to harbor these markers. The AMR markers include SCC mec , mecA and mecC for methicillin, vanA and vanB for vancomycin, bla CTX-M for oxyimino-cephalosporin and aztreonam, and bla KPC for carbapenem resistance. The AMR markers are computationally linked to the pathogens detected, using a statistical model based on observed AMR gene and pathogen abundances. Analytical validation showed high reproducibility (100%), inclusivity (54 to100%), and exclusivity (100%), with limits of detection ranging from 425 to 6,107 pathogen mcfDNA molecules/μL for the different markers. Clinical accuracy was assessed with 115 unique plasma samples from patients at 7 study sites with concordant culture results for 12/18 (66.7%) target bacteria from a variety of specimen types and correlated with available phenotypic antimicrobial susceptibility test results and genotypic results when available. The positive percent agreement (PPA), negative percent agreement (NPA), overall percent agreement (OPA), and diagnostic yield (DY) were estimated for each AMR marker. The results for the combination of SCC mec and mecA for staphylococci were PPA 19/20 (95.0%), NPA 21/22 (95.4%), OPA 40/42 (95.2%), DY 42/60 (70.0%); vanA for enterococci were PPA 3/3 (100%), NPA 2/2 (100%), OPA5/5 (100%), DY 5/6 (83.3%); bla CTX-M for gram-negative bacilli were PPA 5/6 (83.3%), NPA 29/29 (100%), OPA34/35 (97.1%), DY 35/49 (71.4%); and bla KPC for gram-negative bacilli were PPA 0/2 (0%), NPA: 23/23 (100%), OPA23/25 (92.3%), DY 25/44 (56.8%). The addition of AMR capability to plasma mcfDNA sequencing should provide clinicians with an effective new culture-independent tool for optimization of therapy.
2018-05-01 | Bacterial Adaptation to Antibiotics through Regulatory RNAs
The extensive use of antibiotics has resulted in a situation where multidrug-resistant pathogens have become a severe menace to human health worldwide. A deeper understanding of the principles used by pathogens to adapt to, respond to, and resist antibiotics would pave the road to the discovery of drugs with novel mechanisms. For bacteria, antibiotics represent clinically relevant stresses that induce protective responses. The recent implication of regulatory RNAs (small RNAs [sRNAs]) in antibiotic response and resistance in several bacterial pathogens suggests that they should be considered innovative drug targets. This minireview discusses sRNA-mediated mechanisms exploited by bacterial pathogens to fight against antibiotics. A critical discussion of the newest findings in the field is provided, with emphasis on the implication of sRNAs in major mechanisms leading to antibiotic resistance, including drug uptake, active drug efflux, drug target modifications, biofilms, cell walls, and lipopolysaccharide (LPS) biosynthesis. Of interest is the lack of knowledge about sRNAs implicated in Gram-positive compared to Gram-negative bacterial resistance.
2013-03-01 | Antimicrobial Aptamers for Detection and Inhibition of Microbial Pathogen Growth
Discovery of alternative sources of antimicrobial agents are essential in the ongoing battle against microbial pathogens. Legislative and scientific challenges considerably hinder the discovery and use of new antimicrobial drugs, and new approaches are in urgent demand. On the other hand, rapid, specific and sensitive detection of airborne pathogens is becoming increasingly critical for public health. In this respect affinity oligonucleotides, aptamers, provide unique opportunities for the development of nanotechnological solutions for such medical applications. In recent years, aptamers specifically recognizing microbial cells and viruses showed great potential in a range of analytical and therapeutic applications. This article describes the significant advances in the development of aptamers targeting specific pathogens. Therapeutic application of aptamers as neutralizing agents demonstrates great potential as a future source of antimicrobial agent.
2010-06-01 | Antisense Antibiotics: A Brief Review of Novel Target Discovery and Delivery
The nightmare of multi-drug resistant bacteria will still haunt if no panacea is ever found. Efforts on seeking desirable natural products with bactericidal property and screening chemically modified derivatives of traditional antibiotics have lagged behind the emergence of new multi-drug resistant bacteria. The concept of using antisense antibiotics, now as revolutionary as is on threshold has experienced ups and downs in the past decade. In the past five years, however, significant technology advances in the fields of microbial genomics, structural modification of oligonucleotides and efficient delivery system have led to fundamental progress in the research and in vivo application of this paradigm. The wealthy information provided in the microbial genomics era has allowed the identification and/or validation of a number of essential genes that may serve as possible targets for antisense inhibition; antisense oligodeoxynucleotides (ODNs) based on the 3rd generation of modified structures, e.g., peptide nucleic acids (PNAs) and phosphorodiamidate morpholino oligomers (PMOs) have shown great potency in gene expression inhibition in a sequence-specific and dosedependent manner at low micromolar concentrations; and cell penetrating peptide mediated delivery system has enabled the effective display of intracellular antisense inhibition of targeted genes both in vitro and in vivo. The new methods show promise in the discovery of novel gene-specific antisense antibiotics that will be useful in the future battle against drug-resistant bacterial infections. This review describes this promising paradigm, the targets that have been identified and the recent technologies on which it is delivered. Keywords: Antisense oligonucleotides, antisense antibiotics, antibiotic resistance, oligodeoxynucleotides, (ODNs), morpholino oligomers (PMOs), peptide nucleic acids, (PNAs), phosphorodiamidate morpholino oligomers, (PMOs), Staphylococcus aureus, MRSA, Enterococci, VRE, Mycobacterium tuberculosis, Escherichia coli, Klebsiella pneumonia, Pseudomonades, Acinetobacter, pathogenesis, DNA replication, RNA, PS-ODNs, LNAs, Phos phorothioa te DNA, 2'-O-Methox yethyl RNA, (2'-MOE), 2'-O-methyl RNA, Phosphorodiamidate Morpholino, Thiophosphoramidate, Locked Nucleic Acid, Bicyclic Nucleic Acid, β-lactamase, Enterococcus faecalis, Campylobacter jejun, Bacillus anthracis, Mycobacterium smegmatis, Mycobacterium avium, Entamoeba histolytica, Streptococcus mutans, Burkholderia cepacia, Salmonella enterica serovar Typhimurium, gene therapy, gram-negative bacteria, Antibacterial Therapy, Cell penetrating peptide, Pseudomonas aeruginosa, Bacillus subtilis, Corynebacterium efficiens
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Drug Discovery Landscape
1 orphan drug designation for Invasive infections due to vancomycin-resistant enterococci.
1 orphan drug designation for Invasive infections due to vancomycin-resistant enterococci.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Ramoplanin | small molecules | EMA | — | Vicuron Pharmaceuticals Italy srl, |
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