RARE DISEASE
Inhalational anthrax
Inhalational anthrax
Inhalational anthrax
Synonyms: Inhalation anthrax disease, Pulmonary anthrax, Respiratory anthrax, Respiratory anthrax disease
Synonyms: Inhalation anthrax disease, Pulmonary anthrax, Respiratory anthrax, Respiratory anthrax disease
Synonyms: Inhalation anthrax disease, Pulmonary anthrax, Respiratory anthrax, Respiratory anthrax disease
Drug discovery
17
drugs
With orphan designations
Overview
Inhalational anthrax arises from inhaling Bacillus anthracis spores, causing a biphasic illness. Initial flu-like symptoms (fever, cough, fatigue) progress to severe respiratory distress, hemorrhagic mediastinitis, and shock. Mortality remains high (45% post-2001) despite aggressive therapies. Diagnosis relies on blood cultures, PCR, and mediastinal widening on imaging. Early antibiotic/antitoxin initiation improves survival [1][2][16].
Categories: rare infectious diseases
Research Papers
775 drug discovery papers about Inhalational anthrax, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
775 drug discovery papers about Inhalational anthrax, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-17 | In vitro activity and in vivo efficacy of sulopenem against Bacillus anthracis in inhalational anthrax mouse and rabbit models.
Bacillus anthracis is a gram-positive, spore-forming bacterium and the etiological agent of anthrax. As a Tier 1 Select Agent, the pathogen can be isolated from the natural environment, and the endospore is a significant biological threat that can be produced in large quantities, stored, and disseminated by aerosolization. The intentional release of B. anthracis spores has the potential for mass casualties and is a serious threat to public and military health. Fluoroquinolones and tetracyclines are common antibiotics used for post-exposure prophylaxis and treatment in the United States (U.S.), whereas penicillin is the drug of choice throughout the rest of the world. However, these commonly used antibiotics may be contraindicated or suboptimal in a public health crisis. Thus, there is a need for novel medical countermeasures to be developed and tested against B. anthracis. Sulopenem is a broad-spectrum, orally bioavailable penem antibiotic recently approved in the U.S. for the treatment of uncomplicated urinary tract infections in women with limited therapeutic options. Here, we demonstrate that sulopenem has potent in vitro activity against both wild-type virulent B. anthracis strains, as well as biosafety level 2 surrogate strains resistant to current standards of care. Using human-equivalent dosing regimens, we show that sulopenem is highly protective in both the mouse and rabbit inhalational anthrax models. Together, these results support continued evaluation of this oral penem as a countermeasure for inhalational anthrax.
2026-02-12 | Enhancing bioinformatics engineering by utilizing graph therapeutic properties for clinically approved antitoxin drugs in zoonotic diseases
Anthrax, a zoonotic disease caused by the bacterium Bacillus anthracis. It primarily affects animals and spreads to humans through direct contact or inhalation. This article examines the correlations between physicochemical properties and topological indices of the chemical structures of drugs used to mitigate anthrax disease. This study considers the clinically approved drugs, including ciprofloxacin, levaquin, doryx, penicillin tetrapropyl, and pfizerpen, etc. For the chemical structures of these drugs, we have calculated M-polynomials of various reverse topological indices, including the reverse Zagreb-type indices, reverse atom-bond connectivity index, reverse harmonic index, and reverse sum connectivity index, etc. The relationships identified through regression analysis establish quantitative structure-property relationships (QSPR), offering insights into how the molecular structure governs the physical behavior of these antitoxins, which is foundational for future drug optimization efforts. Our findings highlight the regression coefficients that achieved the lowest SE and the maximum $$R^2$$ values, indicating the strongest structure-property correlations (such as for Molecular Weight). These robust coefficients can be used to model the structural properties of chemically similar compounds.
2026-01-01 | P-1180. Effects of a Novel Bacterial Topoisomerase Inhibitor on Type II Topoisomerases in Bacillus anthracis
Abstract Background The tier 1 agent, Bacillus anthracis (etiological cause of anthrax) is a highly transmissible pathogen that causes morbidity and mortality. The intentional release of anthrax spores from either wild-type or drug-resistant strains would constitute a severe threat to public and military health. Novel Bacterial Topoisomerase Inhibitors (NBTIs) are emerging antibacterials that target the type II topoisomerases, gyrase and topoisomerase IV. The NBTI pharmacophore promotes a binding mode that allows for the evasion of target-mediated fluoroquinolone (FQ) resistance. OSUAB0284 is a pre-clinical NBTI candidate that shows potent anti-staphylococcal activity in cultured cells and a neutropenic mouse model.1,2 Gepotidacin is an advanced NBTI-type first-in-class triazaacenapthylene. It has completed phase III clinical trials for the treatment of uncomplicated urogenital gonorrhea with positive outcomes and was approved by the FDA for the treatment of uncomplicated urinary tract infections.3-5Antimicrobial AgentsThe compounds analyzed in this work: ciprofloxacin (FQ), gepotidacin (triazaacenaphthylene), OSUAB0284 (NBTI) Methods Beyond its clinical success, gepotidacin displayed potent activity against wild-type and FQ-resistant strains of B. anthracis in vitro and in vivo.6 Consequently, we analyzed the effects of OSUAB0284 in parallel to ciprofloxacin (an FQ) and gepotidacin in cell- and enzyme-based B. anthracis experiments. Results Ciprofloxacin, gepotidacin, and OSUAB0284 displayed potent antibacterial activity against cultured B. anthracis (MIC90 = 0.06 µg/mL, 0.5 µg/mL, and 0.25 µg/mL, respectively). OSUAB0284 and gepotidacin induced high levels of single-stranded DNA cleavage mediated by purified wild-type B. anthracis gyrase and topoisomerase IV, a mechanism distinct from FQs. DNA cleavage activity was maintained against FQ-resistant gyrase enzymes (GyrAS85L and GyrAE89K). OSUAB0284 and gepotidacin induced even higher levels of DNA cleavage with FQ-resistant topoisomerase IV enzymes (ParCS81Y and ParCE85K) compared to wild-type. OSUAB0284 and gepotidacin inhibited the catalytic function of wild-type B. anthracis gyrase and topoisomerase IV and maintained activity with the FQ-resistant enzymes. Conclusion An inhalation anthrax model in mice treated with OSUAB0284 is ongoing. Our results suggest that NBTIs are potential therapeutic candidates for use against B. anthracis. Disclosures Mark Mitton-Fry, PhD, Pfizer: Stocks/Bonds (Public Company)|Viatris: Stocks/Bonds (Public Company)
2025-12-23 | Activities of the Novel Bacterial Topoisomerase Inhibitor OSUAB-0284 against the Biothreat Pathogen Bacillus anthracis and Its Type II Topoisomerases.
Bacillus anthracis is the etiological agent of anthrax and is classified as a Tier 1 biothreat pathogen. The fluoroquinolone ciprofloxacin is a preferred prophylactic drug for potential anthrax infections and acts by stabilizing DNA strand breaks formed by the bacterial type II topoisomerases, gyrase and topoisomerase IV. Unfortunately, widespread fluoroquinolone usage has increased levels of resistance in common bacterial pathogens, raising concern that resistant B. anthracis strains could be misused. Therefore, there is great interest in developing new classes of antibacterials that are efficacious against both wild-type and fluoroquinolone-resistant B. anthracis infections. Previous studies have demonstrated that gepotidacin, a triazaacenaphthylene antibacterial that targets gyrase and topoisomerase IV, displays potent activity against B. anthracis and was efficacious in a rabbit inhalation anthrax model. Given these promising results, we evaluated the activity of OSUAB-0284, a Novel Bacterial Topoisomerase Inhibitor (NBTI) that shares a general pharmacophore with gepotidacin, against B. anthracis. OSUAB-0284 displayed activity against B. anthracis that was comparable to or better than gepotidacin. Both compounds displayed activity against fluoroquinolone-resistant cells. Gepotidacin and OSUAB-0284 increased levels of gyrase- and topoisomerase IV-mediated DNA single-stranded breaks and inhibited the overall catalytic activity of the two enzymes. Both compounds were also more potent than ciprofloxacin against wild-type gyrase and topoisomerase IV and maintained activity against fluoroquinolone-resistant enzymes. Finally, OSUAB-0284 displayed efficacy in a mouse model of inhalation anthrax. These results provide mechanistic underpinnings supporting the use of gepotidacin and OSUAB-0284 against B. anthracis and suggest that they may be potential candidates for the treatment of anthrax.
2025-05-29 | Development of a System to Deliver Inhalational Antibiotics to Marmosets
Inhalational antibiotics have been used effectively to treat chronic diseases such as Pseudomonas aeruginosa infections associated with cystic fibrosis. This approach may enhance treatment options for difficult-to-treat, acute pneumonic diseases. Liposomal encapsulated ciprofloxacin (Lipoquin and/or Apulmiq) has provided protection in murine models of plague, anthrax, Q fever and tularemia. Development of the ability to deliver these drugs to nonhuman primates (NHPs) would enable further extrapolation of the data observed in small animal models of infection to humans. In this study, the methodology was established to deliver Apulmiq to common marmosets (Callithrix jacchus). Marmosets were anaesthetised with a novel, reversible anaesthetic comprising fentanyl, medetomidine and midazolam (FMM). They were placed into plethysmography tubes with their heads in an exposure chamber. The LC Sprint jet nebuliser or Pari eFlow Rapid nebuliser were used to aerosolise Apulmiq into the exposure chamber. Animals were euthanised after dosing and the concentration of ciprofloxacin was assessed in the plasma and lungs of the animals. Non-compartmental pharmacokinetic analysis determined that a 30 min exposure of drug was required to reach a human-equivalent target dose of 0.8 mg/kg body weight in the lungs. This approach can now be used to assess the efficacy of inhalational liposomal ciprofloxacin in NHP infection models.
proteins
2024-01-31 | Early Circulating Edema Factor in Inhalational Anthrax Infection: Does It Matter?
Anthrax toxins are critical virulence factors of Bacillus anthracis and Bacillus cereus strains that cause anthrax-like disease, composed of a common binding factor, the protective antigen (PA), and two enzymatic proteins, lethal factor (LF) and edema factor (EF). While PA is required for endocytosis and activity of EF and LF, several studies showed that these enzymatic factors disseminate within the body in the absence of PA after intranasal infection. In an effort to understand the impact of EF in the absence of PA, we used a fluorescent EF chimera to facilitate the study of endocytosis in different cell lines. Unexpectedly, EF was found inside cells in the absence of PA and showed a pole-dependent endocytosis. However, looking at enzymatic activity, PA was still required for EF to induce an increase in intracellular cAMP levels. Interestingly, the sequential delivery of EF and then PA rescued the rise in cAMP levels, indicating that PA and EF may functionally associate during intracellular trafficking, as well as it did at the cell surface. Our data shed new light on EF trafficking and the potential location of PA and EF association for optimal cytosolic delivery.
2022-10-15 | Systematic Review of In Vitro Antimicrobial Susceptibility Testing for Bacillus anthracis, 1947-2019.
Bacillus anthracis, the causative agent of anthrax, is a high-consequence bacterial pathogen that occurs naturally in many parts of the world and is considered an agent of biowarfare or bioterrorism. Understanding antimicrobial susceptibility profiles of B. anthracis isolates is foundational to treating naturally occurring outbreaks and to public health preparedness in the event of an intentional release. In this systematic review, we searched the peer-reviewed literature for all publications detailing antimicrobial susceptibility testing of B. anthracis. Within the set of discovered articles, we collated a subset of publications detailing susceptibility testing that followed standardized protocols for Food and Drug Administration-approved, commercially available antimicrobials. We analyzed the findings from the discovered articles, including the reported minimal inhibitory concentrations. Across the literature, most B. anthracis isolates were reported as susceptible to current first-line antimicrobials recommended for postexposure prophylaxis and treatment. The data presented for potential alternative antimicrobials will be of use if significant resistance to first-line antimicrobials arises, the strain is bioengineered, or first-line antimicrobials are not tolerated or available.
2022-04-04 | Insights into antimicrobial peptides in fighting anthrax: A review.
Anthrax is an infectious disease occurring worldwide and is a threat to global society due to its possible misuse as a biological weapon. Bacillus anthracis is the etiologic agent of this disease which can be transmitted via inhalation, ingestion, and skin contact. Globally, it is estimated around 2000 anthrax cases occur per year. Upon infection, the organism can cause cytolysis of macrophage and produce exotoxin capable of inducing edema and lymphatic blockage. Another challenge posed by the organism is the ability to form spores in harsh conditions. Various antibiotics have been used to fight the disease. However, like many other microbes, B. anthracis may develop resistance, thus the discovery of new therapeutics is urgently required. Antimicrobial peptides (AMPs) have been discovered since 1980s and attracted researchers in the antimicrobial field. In this review, the work and studies on the attempts to discover potent AMPs to treat anthrax together with the brief overview of the synthesis and modification pathways of several AMPs have been presented.
2020-11-30 | Comparative Analysis of the Global Transcriptomic Response to Oxidative Stress of Bacillus anthracis htrA-Disrupted and Parental Wild Type Strains
We previously demonstrated that the HtrA (High Temperature Requirement A) protease/chaperone active in the quality control of protein synthesis, represents an important virulence determinant of Bacillus anthracis. Virulence attenuation of htrA-disrupted Bacillus anthracis strains was attributed to susceptibility of ΔhtrA strains to stress insults, as evidenced by affected growth under various stress conditions. Here, we report a comparative RNA-seq transcriptomic study generating a database of differentially expressed genes in the B. anthracis htrA-disrupted and wild type parental strains under oxidative stress. The study demonstrates that, apart from protease and chaperone activities, HtrA exerts a regulatory role influencing expression of more than 1000 genes under stress. Functional analysis of groups or individual genes exhibiting strain-specific modulation, evidenced (i) massive downregulation in the ΔhtrA and upregulation in the WT strains of various transcriptional regulators, (ii) downregulation of translation processes in the WT strain, and (iii) downregulation of metal ion binding functions and upregulation of sporulation-associated functions in the ΔhtrA strain. These modulated functions are extensively discussed. Fifteen genes uniquely upregulated in the wild type strain were further interrogated for their modulation in response to other stress regimens. Overexpression of one of these genes, encoding for MazG (a nucleoside triphosphate pyrophosphohydrolase involved in various stress responses in other bacteria), in the ΔhtrA strain resulted in partial alleviation of the H2O2-sensitive phenotype.
2019-04-01 | Mechanistic insights and therapeutic opportunities of antimicrobial chemokines
Chemokines are a family of small proteins best known for their ability to orchestrate immune cell trafficking and recruitment to sites of infection. Their role in promoting host defense is multiplied by a number of additional receptor-dependent biological activities, and most, but not all, chemokines have been found to mediate direct antimicrobial effects against a broad range of microorganisms. The molecular mechanism(s) by which antimicrobial chemokines kill bacteria remains unknown; however, recent observations have expanded our fundamental understanding of chemokine-mediated bactericidal activity to reveal increasingly diverse and complex actions. In the current review, we present and consider mechanistic insights of chemokine-mediated antimicrobial activity against bacteria. We also discuss how contemporary advances are reshaping traditional paradigms and opening up new and innovative avenues of research with translational implications. Towards this end, we highlight a developing framework for leveraging chemokine-mediated bactericidal and immunomodulatory effects to advance pioneering therapeutic approaches for treating bacterial infections, including those caused by multidrug-resistant pathogens.
vaccines
2026-04-20 | Cytosol-Targeting Delivery of Non-Nucleotide STING Agonist Achieves Inhalable Nanoparticle-Based Anthrax Vaccine.
Inhalational anthrax is a deadly disease caused by inhalation of Bacillus anthracis spores. Current anthrax vaccines for human use have limitations including undefined components, limited mucosal immunity, and suboptimal adjuvant delivery. This study introduces 2 polymers, MP1 and MP2, each containing disulfide bonds. MP1 incorporates tertiary amines to induce proton sponge effect, while MP2 features terminal phenylboronic acid moieties for protein conjugation. Nanoparticle vaccine YM1.7 is created through self-assembly of MP1, MP2, and STING agonist MSA-2, followed by N─B coordination of recombinant protein antigen (rPA) on its surface. When administered via aerosolized intratracheal inoculation into the lung, YM1.7 is internalized by antigen-presenting cell and trafficked to the lysosome, where acidic environment dissociates N─B bond, releasing rPA for antigen presentation. Proton sponge effect allows nanoparticle to escape into the cytosol, and then disulfide bond cleavage triggered by cytosolic glutathione causes dissociation of nanoparticle and release of MSA-2 within the cytosol, significantly enhancing bioavailability of MSA-2 as an adjuvant. This spatiotemporal delivery mechanism elicits a coordinated innate, humoral, mucosal, and cell-mediated immune response in mice, providing strong protection against inhalational anthrax. Given its modular design nature, YM1.7 represents a promising platform for developing next-generation mucosal vaccines against infections and cancers.
2025-08-20 | A Lyophilizable Nanoparticle Vaccine Specific for a Novel Linear Neutralizing Epitope in the α2-α3 Helices of Domain 3 of Lethal Factor from Bacillus anthracis
Anthrax remains a serious bioterrorism threat for which new and thermostable vaccines are needed. We previously demonstrated that immunization of rabbits with multiple-antigenic-peptide (MAP) vaccines elicit antibody (Ab) against the loop-neutralizing-determinant (LND), a cryptic linear neutralizing epitope in the 2β2-2β3 loop of protective antigen (PA) from Bacillus anthracis (B. anthracis), which mediates the complete protection of rabbits from inhalation spore challenge with B. anthracis Ames strain. Importantly, LND-specific Ab is not significantly elicited with PA-based vaccines. In the current study, we sought to identify a second unique neutralizing epitope which would also not overlap with the neutralizing specificities elicited by PA-based vaccines, and which could be combined with an LND vaccine as a prototype bivalent vaccine for anthrax. We evaluated linear peptide sequences in the α2-α3 helices of domain 3 of lethal factor (LF) in the form of virus-like particle (VLP) vaccines. Immunogenicity studies confirmed the presence of a 20-mer peptide sequence that is capable of eliciting protective levels of neutralizing Ab following two immunizations of rabbits using human-use adjuvants, and lyophilization of the VLPs did not diminish their immunogenicity. To our knowledge, this is the first demonstration that immunization with linear peptide sequences from LF can elicit protective levels of neutralizing Ab in vivo.
2025-08-12 | A Lyophilizable Nanoparticle Anthrax Vaccine Targeting the Loop-Neutralizing Determinant in Protective Antigen from Bacillus anthracis
Anthrax remains a formidable bioterrorism threat for which new, optimized and thermostable vaccines are needed. We previously demonstrated that five immunizations of rabbits with a multiple-antigenic-peptide (MAP) vaccine in either Freund's adjuvant or human-use adjuvants can elicit antibody (Ab) against the loop-neutralizing determinant (LND), a cryptic neutralizing epitope in the 2β2-2β3 loop of protective antigen from Bacillus anthracis (B. anthracis), which mediates complete protection of rabbits from inhalation spore challenge with the B. anthracis Ames strain. To develop a more immunogenic vaccine, we molecularly constructed a virus-like particle (VLP) vaccine, comprising the Woodchuck hepatitis core antigen capsid (WHcAg) displaying 240 copies of the LND epitope on each nanoparticle. Initial studies showed that the LND-VLP was immunogenic in rabbits following two immunizations, and passive transfer of the rabbit sera into A/J mice conferred complete protection from aerosol challenge with B. anthracis. Further optimization of the vaccine revealed that the lyophilized LND-VLP vaccine was capable of eliciting highly protective levels of neutralizing antibody with two immunizations, and in some rabbits, a single immunization, using human-use adjuvants. A lyophilized LND-VLP nanoparticle vaccine may be an effective stand-alone vaccine or may complement PA-based vaccines as a future pre- or post-exposure vaccine for anthrax.
2025-05-30 | A Nasal Vaccine Displaying Anthrax Antigen on the Surface of Lactiplantibacillus plantarum Induces Protective Mucosal Immunity against Anthrax Toxin.
Anthrax, particularly inhalational anthrax, poses a severe threat due to its high fatality rate and potential misuse as a biological weapon. Current anthrax vaccines require multiple injections, which limits their practicality and underscores the need for improved, user-friendly vaccination strategies. In this study, we developed a novel nasal booster vaccine platform aimed at preventing inhalational anthrax by inducing mucosal immunity at the pathogen's entry site, the respiratory tract. We successfully engineered a biologically safe Lactiplantibacillus plantarum (L. plantarum) strain to display the anthrax protective antigen (PA) on its surface. Following systemic priming by intramuscular immunization, nasal boosting with this recombinant L. plantarum strain significantly enhanced protective antigen (PA)-specific mucosal IgA production in both nasal and bronchoalveolar lavage fluids. Importantly, mucosal IgA antibodies elicited through this nasal boosting strategy effectively neutralized anthrax lethal toxin. Our findings indicate that recombinant L. plantarum expressing PA represents a promising nasal vaccine booster platform, potentially replacing traditional intramuscular boosters, and paving the way for the development of effective and easily administered mucosal vaccines against anthrax and other respiratory pathogens.
2023-04-04 | Inhalable vaccine of bacterial culture supernatant extract mediates protection against fatal pulmonary anthrax.
Pulmonary anthrax is the most fatal clinical form of anthrax and currently available injectable vaccines do not provide adequate protection against it. Hence, next-generation vaccines that effectively induce immunity against pulmonary anthrax are urgently needed. In the present study, we prepared an attenuated and low protease activity Bacillus anthracis strain A16R-5.1 by deleting five of its extracellular protease activity-associated genes and its lef gene through the CRISPR-Cas9 genome editing system. This mutant strain was then used to formulate a lethal toxin (LeTx)-free culture supernatant extract (CSE) anthrax vaccine, of which half was protective antigen (PA). We generated liquid, powder, and powder reconstituted formulations that could be delivered by aerosolized intratracheal inoculation. All of them induced strong humoral, cellular, and mucosal immune responses. The vaccines also produced LeTx neutralizing antibodies and conferred full protection against the lethal aerosol challenges of B. anthracis Pasteur II spores in mice. Compared to the recombinant PA vaccine, the CSE anthrax vaccine with equal PA content provided superior immunoprotection against pulmonary anthrax. The preceding results suggest that the CSE anthrax vaccine developed herein is suitable and scalable for use in inhalational immunization against pulmonary anthrax.
antibodies
2026-05-21 | Cough
This case describes a patient who comes in with cough and shortness of breath. The course of inhalational anthrax can progress from initial nonspecific viral symptoms to severe respiratory distress, hypotension, hypoxia, tachypnea, cyanosis, and hemorrhage within days. Pathognomonic imaging findings include mediastinal widening due to hemorrhagic mediastinitis, pleural effusion, and mediastinal lymphadenopathy.
2026-01-01 | Epidemiological Investigation and Source Tracing of an Inhalation Anthrax Case with Traceability to Yunnan Province — Guangdong Province, China, March 2026
What is already known about this topic?Anthrax is a zoonotic disease caused by the bacterium Bacillus anthracis (B.anthracis).Inhalation anthrax, caused by inhalation of B. anthracis spores, is the rarest and most fatal form of anthrax.Historically, naturally acquired inhalation anthrax cases have mainly been associated with occupational exposure to infected animals or animal products, such as in wool mills or tanneries. What is added by this report?This report documents the first case of inhalation anthrax in China that was linked to environmental exposure in a historically endemic area, without direct contact with sick animals or animal products.The case was reported in Guangdong Province, however, the source was traced to the patient's newly built residence in Zhenxiong County, Yunnan Province, where environmental samples tested positive for B. anthracis nucleic acid.Three anthrax outbreaks have occurred in this region since 1990. What are the implications for public health practice?In anthrax-endemic areas, environmental exposure to contaminated soil or dust can pose a significant risk of anthrax infection, even without direct animal contact.Although rare, inhalation anthrax can occur naturally as B. anthracis spores can survive extreme environmental conditions in the soil or hay for long periods.As it is difficult to distinguish acute pulmonary infection from inhalational anthrax, severe cases were frequently initially suggested by metagenomic sequencing of the alveolar fluid, with similar findings reported for meningeal anthrax in the cerebrospinal fluid.
2025-12-02 | Infectious Diseases
✓ Gram-Positive Organisms with thick peptidoglycan wall that retains the violet stain Q after washing. Gram-positive cocci Q Staphylococcus aureus (coagulase-positive) Q : Septicaemia, endocarditis, pneumonia, skin sepsis, toxic shock syndrome. Staphylococcus epidermidis (coagulase-negative): Device-related sepsis, sternal wound osteomyelitis. Staphylococcus hominis (coagulase-negative): Device-related sepsis, sternal wound osteomyelitis. Staphylococcus saprophyticus (coagulase-negative): UTIs. Streptococcus pneumoniae ( Pneumococcus ) (α-haemolytic): Community-acquired pneumonia, meningitis, sinusitis. Streptococcus viridans (α-haemolytic): Endocarditis. Streptococcus pyogenes (group A Streptococcus ) ( https://www.w3.org/1998/Math/MathML" display="inline"> β https://www.w3.org/1999/xlink" xlink:href=" https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781003476214/5dedd096-1fa6-4182-bfdf-9420f20eb24a/content/ieq0015.tif "/> -haemolytic): Scarlet fever, rheumatic fever, post-streptococcal glomerulonephritis, puerperal sepsis , necrotizing fasciitis, toxic shock syndrome. Streptococcus agalactiae (group B Streptococcus ) ( https://www.w3.org/1998/Math/MathML" display="inline"> β https://www.w3.org/1999/xlink" xlink:href=" https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781003476214/5dedd096-1fa6-4182-bfdf-9420f20eb24a/content/ieq0016.tif "/> -haemolytic): Neonatal pneumonia and meningitis . Q Streptococcus ( Enterococcus faecium ) ( https://www.w3.org/1998/Math/MathML" display="inline"> γ https://www.w3.org/1999/xlink" xlink:href=" https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781003476214/5dedd096-1fa6-4182-bfdf-9420f20eb24a/content/ieq0017.tif "/> -haemolytic): Endocarditis, UTIs, intra-abdominal infections, wound infection. Streptococcus ( Enterococcus faecalis ) ( https://www.w3.org/1998/Math/MathML" display="inline"> γ https://www.w3.org/1999/xlink" xlink:href=" https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781003476214/5dedd096-1fa6-4182-bfdf-9420f20eb24a/content/ieq0018.tif "/> -haemolytic): Endocarditis, UTIs, intra-abdominal infections, wound infection. Gram-positive bacilli Corynebacterium diphtheriae : Diphtheria. Bacillus anthracis (spore-forming): Cutaneous anthrax, pulmonary anthrax, and gastrointestinal anthrax. Bacillus cereus (spore-forming): Gastrointestinal poisoning which self-terminates in 24 h. Clostridium perfringens (spore-forming anaerobes): Gas gangrene. Clostridium difficile (spore-forming anaerobes): Pseudomembranous colitis. Clostridium botulinum (spore-forming anaerobes): Botulism. Clostridium tetani (spore-forming anaerobes): Tetanus. Listeria monocytogenes : Meningitis in neonates and elderly. Propionibacterium : Skin problems, such as acne vulgaris.
2025-09-01 | Current Understanding on the Biology of <i>Bacillus Anthracis</i> and Its Pathophysiology: A Critical Appraisal
Bacillus anthracis, the causative agent of anthrax, is a Gram-positive bacterium that poses serious concerns for public health and biodefense and capable of forming resilient spores enables prolonged environmental survival, and it can infect hosts through cutaneous, inhalational, gastrointestinal or injection routes. The pathogenicity of bacteria is primarily attributed to its poly-D-glutamic acid capsule and a tripartite exotoxin complex consisting of protective antigen, edema factor and lethal factor, which collectively facilitate immune evasion and systemic spread. While herbivores are particularly vulnerable, all warm-blooded animals, including humans, are susceptible to infection. Natural outbreaks are frequently associated with contaminated soil, making geographic and ecological surveillance essential in endemic regions. Vaccination, particularly with protective antigen (PA)-based vaccines, is the most effective preventive strategy, although challenges in vaccine tolerance and accessibility remain. Recent advances in molecular epidemiology and genomic sequencing have enhanced the tracking of outbreak sources and strain variation. Prompt administration of antimicrobial therapy and monoclonal antibody use are critical for successful treatment. Additionally, proper carcass disposal, environmental decontamination, and active surveillance are crucial for breaking the transmission cycle and managing outbreaks. Understanding the molecular pathogenesis, host susceptibility and immunological responses is essential for advancing diagnostics, therapeutics and control measures.
2023-03-21 | Efficacy of ANTHRASIL (Anthrax Immune Globulin Intravenous (Human)) in rabbit and nonhuman primate models of inhalational anthrax: Data supporting approval under animal rule.
To meet the requirements of the Animal Rule, the efficacy of monotherapy with ANTHRASIL® (Anthrax Immune Globulin Intravenous (Human)) for inhalational anthrax was evaluated in blinded studies using rabbit and nonhuman primate models. Animals in both studies were randomized to treatment groups exposed to ~ 200 LD50 Bacillus anthracis (Ames strain) spores by the aerosol route to induce inhalational anthrax. Rabbits (N = 50/group) were treated with either 15 U/kg ANTHRASIL or a volume-matching dose of IGIV after disease onset as determined by the detection of bacterial toxin in the blood. At the end of the study, survival rates were 2% (1 of 48) in the IGIV control group, and 26% (13 of 50) in the ANTHRASIL-treated group (p = 0.0009). Similarly, ANTHRASIL was effective in cynomolgus monkeys (N = 16/group) when administered therapeutically after the onset of toxemia, with 6% survival in the IGIV control and a dose-related increase in survival of 36%, 43%, and 70% with 7.5, 15 or 30 U/kg doses of ANTHRASIL, respectively. These studies formed the basis for approval of ANTHRASIL by FDA under the Animal Rule.
other
2024-07-20 | Flexible RNA aptamers as inhibitors of Bacillus anthracis ribosomal protein S8: Insights from molecular dynamics simulations.
Bacillus anthracis, the causative agent of anthrax, poses a substantial threat to public health and national security, and is recognized as a potential bioweapon due to its capacity to form resilient spores with enduring viability. Inhalation or ingestion of even minute quantities of aerosolized spores can lead to widespread illness and fatalities, underscoring the formidable lethality of the bacterium. With an untreated mortality rate of 100%, Bacillus anthracis is a disconcerting candidate for bioterrorism. In response to this critical scenario, we employed state-of-the-art computational tools to conceive and characterize flexible RNA aptamer therapeutics tailored for anthrax. The foundational structure of the flexible RNA aptamers was designed by removing the C2'-C3' in each nucleotide unit. Leveraging the crystal structure of Bacillus anthracis ribosomal protein S8 complexed with an RNA aptamer, we explored the structural, dynamic, and energetic aspects of the modified RNA aptamer - S8 protein complexes through extensive all-atom explicit-solvent molecular dynamics simulations (400 ns, 3 replicas each), followed by drawing comparisons to the control system. Our findings demonstrate the enhanced binding competencies of the flexible RNA aptamers to the S8 protein via better shape complementarity and improved H-bond network compared to the control RNA aptamer. This research offers valuable insights into the development of RNA aptamer therapeutics targeting Bacillus anthracis, paving the way for innovative strategies to mitigate the impact of this formidable pathogen.
2024-04-27 | Investigating the Influence of ANTXR2 Gene Mutations on Protective Antigen Binding for Heightened Anthrax Resistance.
Bacillus anthracis is the bacterium responsible for causing the zoonotic disease called anthrax. The disease presents itself in different forms like gastrointestinal, inhalation, and cutaneous. Bacterial spores are tremendously adaptable, can persist for extended periods and occasionally endanger human health. The Anthrax Toxin Receptor-2 (ANTXR2) gene acts as membrane receptor and facilitates the entry of the anthrax toxin into host cells. Additionally, mutations in the ANTXR2 gene have been linked to various autoimmune diseases, including Hyaline Fibromatosis Syndrome (HFS), Ankylosing Spondylitis (AS), Juvenile Hyaline Fibromatosis (JHF), and Infantile Systemic Hyalinosis (ISH). This study delves into the genetic landscape of ANTXR2, aiming to comprehend its associations with diverse disorders, elucidate the impacts of its mutations, and pinpoint minimal non-pathogenic mutations capable of reducing the binding affinity of the ANTXR2 gene with the protective antigen. Recognizing the pivotal role of single-nucleotide polymorphisms (SNPs) in shaping genetic diversity, we conducted computational analyses to discern highly deleterious and tolerated non-synonymous SNPs (nsSNPs) in the ANTXR2 gene. The Mutpred2 server determined that the Arg465Trp alteration in the ANTXR2 gene leads to altered DNA binding (p = 0.22) with a probability of a deleterious mutation of 0.808; notably, among the identified deleterious SNPs, rs368288611 (Arg465Trp) stands out due to its significant impact on altering the DNA-binding ability of ANTXR2. We propose these SNPs as potential candidates for hypertension linked to the ANTXR2 gene, which is implicated in blood pressure regulation. Noteworthy among the tolerated substitutions is rs200536829 (Ala33Ser), recognized as less pathogenic; this highlights its potential as a valuable biomarker, potentially reducing side effects on the host while also reducing binding with the protective antigen protein. Investigating these SNPs holds the potential to correlate with several autoimmune disorders and mitigate the impact of anthrax disease in humans.
2016-08-01 | Gene control of tyrosine kinase TIE2 and vascular manifestations of infections.
Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.
2014-04-18 | Targeted Silencing of Anthrax Toxin Receptors Protects against Anthrax Toxins
Anthrax spores can be aerosolized and dispersed as a bioweapon. Current postexposure treatments are inadequate at later stages of infection, when high levels of anthrax toxins are present. Anthrax toxins enter cells via two identified anthrax toxin receptors: tumor endothelial marker 8 (TEM8) and capillary morphogenesis protein 2 (CMG2). We hypothesized that host cells would be protected from anthrax toxins if anthrax toxin receptor expression was effectively silenced using RNA interference (RNAi) technology. Thus, anthrax toxin receptors in mouse and human macrophages were silenced using targeted siRNAs or blocked with specific antibody prior to challenge with anthrax lethal toxin. Viability assays were used to assess protection in macrophages treated with specific siRNA or antibody as compared with untreated cells. Silencing CMG2 using targeted siRNAs provided almost complete protection against anthrax lethal toxin-induced cytotoxicity and death in murine and human macrophages. The same results were obtained by prebinding cells with specific antibody prior to treatment with anthrax lethal toxin. In addition, TEM8-targeted siRNAs also offered significant protection against lethal toxin in human macrophage-like cells. Furthermore, silencing CMG2, TEM8, or both receptors in combination was also protective against MEK2 cleavage by lethal toxin or adenylyl cyclase activity by edema toxin in human kidney cells. Thus, anthrax toxin receptor-targeted RNAi has the potential to be developed as a life-saving, postexposure therapy against anthrax. Anthrax spores can be aerosolized and dispersed as a bioweapon. Current postexposure treatments are inadequate at later stages of infection, when high levels of anthrax toxins are present. Anthrax toxins enter cells via two identified anthrax toxin receptors: tumor endothelial marker 8 (TEM8) and capillary morphogenesis protein 2 (CMG2). We hypothesized that host cells would be protected from anthrax toxins if anthrax toxin receptor expression was effectively silenced using RNA interference (RNAi) technology. Thus, anthrax toxin receptors in mouse and human macrophages were silenced using targeted siRNAs or blocked with specific antibody prior to challenge with anthrax lethal toxin. Viability assays were used to assess protection in macrophages treated with specific siRNA or antibody as compared with untreated cells. Silencing CMG2 using targeted siRNAs provided almost complete protection against anthrax lethal toxin-induced cytotoxicity and death in murine and human macrophages. The same results were obtained by prebinding cells with specific antibody prior to treatment with anthrax lethal toxin. In addition, TEM8-targeted siRNAs also offered significant protection against lethal toxin in human macrophage-like cells. Furthermore, silencing CMG2, TEM8, or both receptors in combination was also protective against MEK2 cleavage by lethal toxin or adenylyl cyclase activity by edema toxin in human kidney cells. Thus, anthrax toxin receptor-targeted RNAi has the potential to be developed as a life-saving, postexposure therapy against anthrax.
2013-09-18 | Rapid targeted gene disruption in Bacillus anthracis
Abstract Background Anthrax is a zoonotic disease recognized to affect herbivores since Biblical times and has the widest range of susceptible host species of any known pathogen. The ease with which the bacterium can be weaponized and its recent deliberate use as an agent of terror, have highlighted the importance of gaining a deeper understanding and effective countermeasures for this important pathogen. High quality sequence data has opened the possibility of systematic dissection of how genes distributed on both the bacterial chromosome and associated plasmids have made it such a successful pathogen. However, low transformation efficiency and relatively few genetic tools for chromosomal manipulation have hampered full interrogation of its genome. Results Group II introns have been developed into an efficient tool for site-specific gene inactivation in several organisms. We have adapted group II intron targeting technology for application in Bacillus anthracis and generated vectors that permit gene inactivation through group II intron insertion. The vectors developed permit screening for the desired insertion through PCR or direct selection of intron insertions using a selection scheme that activates a kanamycin resistance marker upon successful intron insertion. Conclusions The design and vector construction described here provides a useful tool for high throughput experimental interrogation of the Bacillus anthracis genome and will benefit efforts to develop improved vaccines and therapeutics.
small molecules
2026-07-17 | In vitro activity and in vivo efficacy of sulopenem against Bacillus anthracis in inhalational anthrax mouse and rabbit models.
Bacillus anthracis is a gram-positive, spore-forming bacterium and the etiological agent of anthrax. As a Tier 1 Select Agent, the pathogen can be isolated from the natural environment, and the endospore is a significant biological threat that can be produced in large quantities, stored, and disseminated by aerosolization. The intentional release of B. anthracis spores has the potential for mass casualties and is a serious threat to public and military health. Fluoroquinolones and tetracyclines are common antibiotics used for post-exposure prophylaxis and treatment in the United States (U.S.), whereas penicillin is the drug of choice throughout the rest of the world. However, these commonly used antibiotics may be contraindicated or suboptimal in a public health crisis. Thus, there is a need for novel medical countermeasures to be developed and tested against B. anthracis. Sulopenem is a broad-spectrum, orally bioavailable penem antibiotic recently approved in the U.S. for the treatment of uncomplicated urinary tract infections in women with limited therapeutic options. Here, we demonstrate that sulopenem has potent in vitro activity against both wild-type virulent B. anthracis strains, as well as biosafety level 2 surrogate strains resistant to current standards of care. Using human-equivalent dosing regimens, we show that sulopenem is highly protective in both the mouse and rabbit inhalational anthrax models. Together, these results support continued evaluation of this oral penem as a countermeasure for inhalational anthrax.
2026-02-12 | Enhancing bioinformatics engineering by utilizing graph therapeutic properties for clinically approved antitoxin drugs in zoonotic diseases
Anthrax, a zoonotic disease caused by the bacterium Bacillus anthracis. It primarily affects animals and spreads to humans through direct contact or inhalation. This article examines the correlations between physicochemical properties and topological indices of the chemical structures of drugs used to mitigate anthrax disease. This study considers the clinically approved drugs, including ciprofloxacin, levaquin, doryx, penicillin tetrapropyl, and pfizerpen, etc. For the chemical structures of these drugs, we have calculated M-polynomials of various reverse topological indices, including the reverse Zagreb-type indices, reverse atom-bond connectivity index, reverse harmonic index, and reverse sum connectivity index, etc. The relationships identified through regression analysis establish quantitative structure-property relationships (QSPR), offering insights into how the molecular structure governs the physical behavior of these antitoxins, which is foundational for future drug optimization efforts. Our findings highlight the regression coefficients that achieved the lowest SE and the maximum $$R^2$$ values, indicating the strongest structure-property correlations (such as for Molecular Weight). These robust coefficients can be used to model the structural properties of chemically similar compounds.
2026-01-01 | P-1180. Effects of a Novel Bacterial Topoisomerase Inhibitor on Type II Topoisomerases in Bacillus anthracis
Abstract Background The tier 1 agent, Bacillus anthracis (etiological cause of anthrax) is a highly transmissible pathogen that causes morbidity and mortality. The intentional release of anthrax spores from either wild-type or drug-resistant strains would constitute a severe threat to public and military health. Novel Bacterial Topoisomerase Inhibitors (NBTIs) are emerging antibacterials that target the type II topoisomerases, gyrase and topoisomerase IV. The NBTI pharmacophore promotes a binding mode that allows for the evasion of target-mediated fluoroquinolone (FQ) resistance. OSUAB0284 is a pre-clinical NBTI candidate that shows potent anti-staphylococcal activity in cultured cells and a neutropenic mouse model.1,2 Gepotidacin is an advanced NBTI-type first-in-class triazaacenapthylene. It has completed phase III clinical trials for the treatment of uncomplicated urogenital gonorrhea with positive outcomes and was approved by the FDA for the treatment of uncomplicated urinary tract infections.3-5Antimicrobial AgentsThe compounds analyzed in this work: ciprofloxacin (FQ), gepotidacin (triazaacenaphthylene), OSUAB0284 (NBTI) Methods Beyond its clinical success, gepotidacin displayed potent activity against wild-type and FQ-resistant strains of B. anthracis in vitro and in vivo.6 Consequently, we analyzed the effects of OSUAB0284 in parallel to ciprofloxacin (an FQ) and gepotidacin in cell- and enzyme-based B. anthracis experiments. Results Ciprofloxacin, gepotidacin, and OSUAB0284 displayed potent antibacterial activity against cultured B. anthracis (MIC90 = 0.06 µg/mL, 0.5 µg/mL, and 0.25 µg/mL, respectively). OSUAB0284 and gepotidacin induced high levels of single-stranded DNA cleavage mediated by purified wild-type B. anthracis gyrase and topoisomerase IV, a mechanism distinct from FQs. DNA cleavage activity was maintained against FQ-resistant gyrase enzymes (GyrAS85L and GyrAE89K). OSUAB0284 and gepotidacin induced even higher levels of DNA cleavage with FQ-resistant topoisomerase IV enzymes (ParCS81Y and ParCE85K) compared to wild-type. OSUAB0284 and gepotidacin inhibited the catalytic function of wild-type B. anthracis gyrase and topoisomerase IV and maintained activity with the FQ-resistant enzymes. Conclusion An inhalation anthrax model in mice treated with OSUAB0284 is ongoing. Our results suggest that NBTIs are potential therapeutic candidates for use against B. anthracis. Disclosures Mark Mitton-Fry, PhD, Pfizer: Stocks/Bonds (Public Company)|Viatris: Stocks/Bonds (Public Company)
2025-12-23 | Activities of the Novel Bacterial Topoisomerase Inhibitor OSUAB-0284 against the Biothreat Pathogen Bacillus anthracis and Its Type II Topoisomerases.
Bacillus anthracis is the etiological agent of anthrax and is classified as a Tier 1 biothreat pathogen. The fluoroquinolone ciprofloxacin is a preferred prophylactic drug for potential anthrax infections and acts by stabilizing DNA strand breaks formed by the bacterial type II topoisomerases, gyrase and topoisomerase IV. Unfortunately, widespread fluoroquinolone usage has increased levels of resistance in common bacterial pathogens, raising concern that resistant B. anthracis strains could be misused. Therefore, there is great interest in developing new classes of antibacterials that are efficacious against both wild-type and fluoroquinolone-resistant B. anthracis infections. Previous studies have demonstrated that gepotidacin, a triazaacenaphthylene antibacterial that targets gyrase and topoisomerase IV, displays potent activity against B. anthracis and was efficacious in a rabbit inhalation anthrax model. Given these promising results, we evaluated the activity of OSUAB-0284, a Novel Bacterial Topoisomerase Inhibitor (NBTI) that shares a general pharmacophore with gepotidacin, against B. anthracis. OSUAB-0284 displayed activity against B. anthracis that was comparable to or better than gepotidacin. Both compounds displayed activity against fluoroquinolone-resistant cells. Gepotidacin and OSUAB-0284 increased levels of gyrase- and topoisomerase IV-mediated DNA single-stranded breaks and inhibited the overall catalytic activity of the two enzymes. Both compounds were also more potent than ciprofloxacin against wild-type gyrase and topoisomerase IV and maintained activity against fluoroquinolone-resistant enzymes. Finally, OSUAB-0284 displayed efficacy in a mouse model of inhalation anthrax. These results provide mechanistic underpinnings supporting the use of gepotidacin and OSUAB-0284 against B. anthracis and suggest that they may be potential candidates for the treatment of anthrax.
2025-05-29 | Development of a System to Deliver Inhalational Antibiotics to Marmosets
Inhalational antibiotics have been used effectively to treat chronic diseases such as Pseudomonas aeruginosa infections associated with cystic fibrosis. This approach may enhance treatment options for difficult-to-treat, acute pneumonic diseases. Liposomal encapsulated ciprofloxacin (Lipoquin and/or Apulmiq) has provided protection in murine models of plague, anthrax, Q fever and tularemia. Development of the ability to deliver these drugs to nonhuman primates (NHPs) would enable further extrapolation of the data observed in small animal models of infection to humans. In this study, the methodology was established to deliver Apulmiq to common marmosets (Callithrix jacchus). Marmosets were anaesthetised with a novel, reversible anaesthetic comprising fentanyl, medetomidine and midazolam (FMM). They were placed into plethysmography tubes with their heads in an exposure chamber. The LC Sprint jet nebuliser or Pari eFlow Rapid nebuliser were used to aerosolise Apulmiq into the exposure chamber. Animals were euthanised after dosing and the concentration of ciprofloxacin was assessed in the plasma and lungs of the animals. Non-compartmental pharmacokinetic analysis determined that a 30 min exposure of drug was required to reach a human-equivalent target dose of 0.8 mg/kg body weight in the lungs. This approach can now be used to assess the efficacy of inhalational liposomal ciprofloxacin in NHP infection models.
proteins
2024-01-31 | Early Circulating Edema Factor in Inhalational Anthrax Infection: Does It Matter?
Anthrax toxins are critical virulence factors of Bacillus anthracis and Bacillus cereus strains that cause anthrax-like disease, composed of a common binding factor, the protective antigen (PA), and two enzymatic proteins, lethal factor (LF) and edema factor (EF). While PA is required for endocytosis and activity of EF and LF, several studies showed that these enzymatic factors disseminate within the body in the absence of PA after intranasal infection. In an effort to understand the impact of EF in the absence of PA, we used a fluorescent EF chimera to facilitate the study of endocytosis in different cell lines. Unexpectedly, EF was found inside cells in the absence of PA and showed a pole-dependent endocytosis. However, looking at enzymatic activity, PA was still required for EF to induce an increase in intracellular cAMP levels. Interestingly, the sequential delivery of EF and then PA rescued the rise in cAMP levels, indicating that PA and EF may functionally associate during intracellular trafficking, as well as it did at the cell surface. Our data shed new light on EF trafficking and the potential location of PA and EF association for optimal cytosolic delivery.
2022-10-15 | Systematic Review of In Vitro Antimicrobial Susceptibility Testing for Bacillus anthracis, 1947-2019.
Bacillus anthracis, the causative agent of anthrax, is a high-consequence bacterial pathogen that occurs naturally in many parts of the world and is considered an agent of biowarfare or bioterrorism. Understanding antimicrobial susceptibility profiles of B. anthracis isolates is foundational to treating naturally occurring outbreaks and to public health preparedness in the event of an intentional release. In this systematic review, we searched the peer-reviewed literature for all publications detailing antimicrobial susceptibility testing of B. anthracis. Within the set of discovered articles, we collated a subset of publications detailing susceptibility testing that followed standardized protocols for Food and Drug Administration-approved, commercially available antimicrobials. We analyzed the findings from the discovered articles, including the reported minimal inhibitory concentrations. Across the literature, most B. anthracis isolates were reported as susceptible to current first-line antimicrobials recommended for postexposure prophylaxis and treatment. The data presented for potential alternative antimicrobials will be of use if significant resistance to first-line antimicrobials arises, the strain is bioengineered, or first-line antimicrobials are not tolerated or available.
2022-04-04 | Insights into antimicrobial peptides in fighting anthrax: A review.
Anthrax is an infectious disease occurring worldwide and is a threat to global society due to its possible misuse as a biological weapon. Bacillus anthracis is the etiologic agent of this disease which can be transmitted via inhalation, ingestion, and skin contact. Globally, it is estimated around 2000 anthrax cases occur per year. Upon infection, the organism can cause cytolysis of macrophage and produce exotoxin capable of inducing edema and lymphatic blockage. Another challenge posed by the organism is the ability to form spores in harsh conditions. Various antibiotics have been used to fight the disease. However, like many other microbes, B. anthracis may develop resistance, thus the discovery of new therapeutics is urgently required. Antimicrobial peptides (AMPs) have been discovered since 1980s and attracted researchers in the antimicrobial field. In this review, the work and studies on the attempts to discover potent AMPs to treat anthrax together with the brief overview of the synthesis and modification pathways of several AMPs have been presented.
2020-11-30 | Comparative Analysis of the Global Transcriptomic Response to Oxidative Stress of Bacillus anthracis htrA-Disrupted and Parental Wild Type Strains
We previously demonstrated that the HtrA (High Temperature Requirement A) protease/chaperone active in the quality control of protein synthesis, represents an important virulence determinant of Bacillus anthracis. Virulence attenuation of htrA-disrupted Bacillus anthracis strains was attributed to susceptibility of ΔhtrA strains to stress insults, as evidenced by affected growth under various stress conditions. Here, we report a comparative RNA-seq transcriptomic study generating a database of differentially expressed genes in the B. anthracis htrA-disrupted and wild type parental strains under oxidative stress. The study demonstrates that, apart from protease and chaperone activities, HtrA exerts a regulatory role influencing expression of more than 1000 genes under stress. Functional analysis of groups or individual genes exhibiting strain-specific modulation, evidenced (i) massive downregulation in the ΔhtrA and upregulation in the WT strains of various transcriptional regulators, (ii) downregulation of translation processes in the WT strain, and (iii) downregulation of metal ion binding functions and upregulation of sporulation-associated functions in the ΔhtrA strain. These modulated functions are extensively discussed. Fifteen genes uniquely upregulated in the wild type strain were further interrogated for their modulation in response to other stress regimens. Overexpression of one of these genes, encoding for MazG (a nucleoside triphosphate pyrophosphohydrolase involved in various stress responses in other bacteria), in the ΔhtrA strain resulted in partial alleviation of the H2O2-sensitive phenotype.
2019-04-01 | Mechanistic insights and therapeutic opportunities of antimicrobial chemokines
Chemokines are a family of small proteins best known for their ability to orchestrate immune cell trafficking and recruitment to sites of infection. Their role in promoting host defense is multiplied by a number of additional receptor-dependent biological activities, and most, but not all, chemokines have been found to mediate direct antimicrobial effects against a broad range of microorganisms. The molecular mechanism(s) by which antimicrobial chemokines kill bacteria remains unknown; however, recent observations have expanded our fundamental understanding of chemokine-mediated bactericidal activity to reveal increasingly diverse and complex actions. In the current review, we present and consider mechanistic insights of chemokine-mediated antimicrobial activity against bacteria. We also discuss how contemporary advances are reshaping traditional paradigms and opening up new and innovative avenues of research with translational implications. Towards this end, we highlight a developing framework for leveraging chemokine-mediated bactericidal and immunomodulatory effects to advance pioneering therapeutic approaches for treating bacterial infections, including those caused by multidrug-resistant pathogens.
vaccines
2026-04-20 | Cytosol-Targeting Delivery of Non-Nucleotide STING Agonist Achieves Inhalable Nanoparticle-Based Anthrax Vaccine.
Inhalational anthrax is a deadly disease caused by inhalation of Bacillus anthracis spores. Current anthrax vaccines for human use have limitations including undefined components, limited mucosal immunity, and suboptimal adjuvant delivery. This study introduces 2 polymers, MP1 and MP2, each containing disulfide bonds. MP1 incorporates tertiary amines to induce proton sponge effect, while MP2 features terminal phenylboronic acid moieties for protein conjugation. Nanoparticle vaccine YM1.7 is created through self-assembly of MP1, MP2, and STING agonist MSA-2, followed by N─B coordination of recombinant protein antigen (rPA) on its surface. When administered via aerosolized intratracheal inoculation into the lung, YM1.7 is internalized by antigen-presenting cell and trafficked to the lysosome, where acidic environment dissociates N─B bond, releasing rPA for antigen presentation. Proton sponge effect allows nanoparticle to escape into the cytosol, and then disulfide bond cleavage triggered by cytosolic glutathione causes dissociation of nanoparticle and release of MSA-2 within the cytosol, significantly enhancing bioavailability of MSA-2 as an adjuvant. This spatiotemporal delivery mechanism elicits a coordinated innate, humoral, mucosal, and cell-mediated immune response in mice, providing strong protection against inhalational anthrax. Given its modular design nature, YM1.7 represents a promising platform for developing next-generation mucosal vaccines against infections and cancers.
2025-08-20 | A Lyophilizable Nanoparticle Vaccine Specific for a Novel Linear Neutralizing Epitope in the α2-α3 Helices of Domain 3 of Lethal Factor from Bacillus anthracis
Anthrax remains a serious bioterrorism threat for which new and thermostable vaccines are needed. We previously demonstrated that immunization of rabbits with multiple-antigenic-peptide (MAP) vaccines elicit antibody (Ab) against the loop-neutralizing-determinant (LND), a cryptic linear neutralizing epitope in the 2β2-2β3 loop of protective antigen (PA) from Bacillus anthracis (B. anthracis), which mediates the complete protection of rabbits from inhalation spore challenge with B. anthracis Ames strain. Importantly, LND-specific Ab is not significantly elicited with PA-based vaccines. In the current study, we sought to identify a second unique neutralizing epitope which would also not overlap with the neutralizing specificities elicited by PA-based vaccines, and which could be combined with an LND vaccine as a prototype bivalent vaccine for anthrax. We evaluated linear peptide sequences in the α2-α3 helices of domain 3 of lethal factor (LF) in the form of virus-like particle (VLP) vaccines. Immunogenicity studies confirmed the presence of a 20-mer peptide sequence that is capable of eliciting protective levels of neutralizing Ab following two immunizations of rabbits using human-use adjuvants, and lyophilization of the VLPs did not diminish their immunogenicity. To our knowledge, this is the first demonstration that immunization with linear peptide sequences from LF can elicit protective levels of neutralizing Ab in vivo.
2025-08-12 | A Lyophilizable Nanoparticle Anthrax Vaccine Targeting the Loop-Neutralizing Determinant in Protective Antigen from Bacillus anthracis
Anthrax remains a formidable bioterrorism threat for which new, optimized and thermostable vaccines are needed. We previously demonstrated that five immunizations of rabbits with a multiple-antigenic-peptide (MAP) vaccine in either Freund's adjuvant or human-use adjuvants can elicit antibody (Ab) against the loop-neutralizing determinant (LND), a cryptic neutralizing epitope in the 2β2-2β3 loop of protective antigen from Bacillus anthracis (B. anthracis), which mediates complete protection of rabbits from inhalation spore challenge with the B. anthracis Ames strain. To develop a more immunogenic vaccine, we molecularly constructed a virus-like particle (VLP) vaccine, comprising the Woodchuck hepatitis core antigen capsid (WHcAg) displaying 240 copies of the LND epitope on each nanoparticle. Initial studies showed that the LND-VLP was immunogenic in rabbits following two immunizations, and passive transfer of the rabbit sera into A/J mice conferred complete protection from aerosol challenge with B. anthracis. Further optimization of the vaccine revealed that the lyophilized LND-VLP vaccine was capable of eliciting highly protective levels of neutralizing antibody with two immunizations, and in some rabbits, a single immunization, using human-use adjuvants. A lyophilized LND-VLP nanoparticle vaccine may be an effective stand-alone vaccine or may complement PA-based vaccines as a future pre- or post-exposure vaccine for anthrax.
2025-05-30 | A Nasal Vaccine Displaying Anthrax Antigen on the Surface of Lactiplantibacillus plantarum Induces Protective Mucosal Immunity against Anthrax Toxin.
Anthrax, particularly inhalational anthrax, poses a severe threat due to its high fatality rate and potential misuse as a biological weapon. Current anthrax vaccines require multiple injections, which limits their practicality and underscores the need for improved, user-friendly vaccination strategies. In this study, we developed a novel nasal booster vaccine platform aimed at preventing inhalational anthrax by inducing mucosal immunity at the pathogen's entry site, the respiratory tract. We successfully engineered a biologically safe Lactiplantibacillus plantarum (L. plantarum) strain to display the anthrax protective antigen (PA) on its surface. Following systemic priming by intramuscular immunization, nasal boosting with this recombinant L. plantarum strain significantly enhanced protective antigen (PA)-specific mucosal IgA production in both nasal and bronchoalveolar lavage fluids. Importantly, mucosal IgA antibodies elicited through this nasal boosting strategy effectively neutralized anthrax lethal toxin. Our findings indicate that recombinant L. plantarum expressing PA represents a promising nasal vaccine booster platform, potentially replacing traditional intramuscular boosters, and paving the way for the development of effective and easily administered mucosal vaccines against anthrax and other respiratory pathogens.
2023-04-04 | Inhalable vaccine of bacterial culture supernatant extract mediates protection against fatal pulmonary anthrax.
Pulmonary anthrax is the most fatal clinical form of anthrax and currently available injectable vaccines do not provide adequate protection against it. Hence, next-generation vaccines that effectively induce immunity against pulmonary anthrax are urgently needed. In the present study, we prepared an attenuated and low protease activity Bacillus anthracis strain A16R-5.1 by deleting five of its extracellular protease activity-associated genes and its lef gene through the CRISPR-Cas9 genome editing system. This mutant strain was then used to formulate a lethal toxin (LeTx)-free culture supernatant extract (CSE) anthrax vaccine, of which half was protective antigen (PA). We generated liquid, powder, and powder reconstituted formulations that could be delivered by aerosolized intratracheal inoculation. All of them induced strong humoral, cellular, and mucosal immune responses. The vaccines also produced LeTx neutralizing antibodies and conferred full protection against the lethal aerosol challenges of B. anthracis Pasteur II spores in mice. Compared to the recombinant PA vaccine, the CSE anthrax vaccine with equal PA content provided superior immunoprotection against pulmonary anthrax. The preceding results suggest that the CSE anthrax vaccine developed herein is suitable and scalable for use in inhalational immunization against pulmonary anthrax.
antibodies
2026-05-21 | Cough
This case describes a patient who comes in with cough and shortness of breath. The course of inhalational anthrax can progress from initial nonspecific viral symptoms to severe respiratory distress, hypotension, hypoxia, tachypnea, cyanosis, and hemorrhage within days. Pathognomonic imaging findings include mediastinal widening due to hemorrhagic mediastinitis, pleural effusion, and mediastinal lymphadenopathy.
2026-01-01 | Epidemiological Investigation and Source Tracing of an Inhalation Anthrax Case with Traceability to Yunnan Province — Guangdong Province, China, March 2026
What is already known about this topic?Anthrax is a zoonotic disease caused by the bacterium Bacillus anthracis (B.anthracis).Inhalation anthrax, caused by inhalation of B. anthracis spores, is the rarest and most fatal form of anthrax.Historically, naturally acquired inhalation anthrax cases have mainly been associated with occupational exposure to infected animals or animal products, such as in wool mills or tanneries. What is added by this report?This report documents the first case of inhalation anthrax in China that was linked to environmental exposure in a historically endemic area, without direct contact with sick animals or animal products.The case was reported in Guangdong Province, however, the source was traced to the patient's newly built residence in Zhenxiong County, Yunnan Province, where environmental samples tested positive for B. anthracis nucleic acid.Three anthrax outbreaks have occurred in this region since 1990. What are the implications for public health practice?In anthrax-endemic areas, environmental exposure to contaminated soil or dust can pose a significant risk of anthrax infection, even without direct animal contact.Although rare, inhalation anthrax can occur naturally as B. anthracis spores can survive extreme environmental conditions in the soil or hay for long periods.As it is difficult to distinguish acute pulmonary infection from inhalational anthrax, severe cases were frequently initially suggested by metagenomic sequencing of the alveolar fluid, with similar findings reported for meningeal anthrax in the cerebrospinal fluid.
2025-12-02 | Infectious Diseases
✓ Gram-Positive Organisms with thick peptidoglycan wall that retains the violet stain Q after washing. Gram-positive cocci Q Staphylococcus aureus (coagulase-positive) Q : Septicaemia, endocarditis, pneumonia, skin sepsis, toxic shock syndrome. Staphylococcus epidermidis (coagulase-negative): Device-related sepsis, sternal wound osteomyelitis. Staphylococcus hominis (coagulase-negative): Device-related sepsis, sternal wound osteomyelitis. Staphylococcus saprophyticus (coagulase-negative): UTIs. Streptococcus pneumoniae ( Pneumococcus ) (α-haemolytic): Community-acquired pneumonia, meningitis, sinusitis. Streptococcus viridans (α-haemolytic): Endocarditis. Streptococcus pyogenes (group A Streptococcus ) ( https://www.w3.org/1998/Math/MathML" display="inline"> β https://www.w3.org/1999/xlink" xlink:href=" https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781003476214/5dedd096-1fa6-4182-bfdf-9420f20eb24a/content/ieq0015.tif "/> -haemolytic): Scarlet fever, rheumatic fever, post-streptococcal glomerulonephritis, puerperal sepsis , necrotizing fasciitis, toxic shock syndrome. Streptococcus agalactiae (group B Streptococcus ) ( https://www.w3.org/1998/Math/MathML" display="inline"> β https://www.w3.org/1999/xlink" xlink:href=" https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781003476214/5dedd096-1fa6-4182-bfdf-9420f20eb24a/content/ieq0016.tif "/> -haemolytic): Neonatal pneumonia and meningitis . Q Streptococcus ( Enterococcus faecium ) ( https://www.w3.org/1998/Math/MathML" display="inline"> γ https://www.w3.org/1999/xlink" xlink:href=" https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781003476214/5dedd096-1fa6-4182-bfdf-9420f20eb24a/content/ieq0017.tif "/> -haemolytic): Endocarditis, UTIs, intra-abdominal infections, wound infection. Streptococcus ( Enterococcus faecalis ) ( https://www.w3.org/1998/Math/MathML" display="inline"> γ https://www.w3.org/1999/xlink" xlink:href=" https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781003476214/5dedd096-1fa6-4182-bfdf-9420f20eb24a/content/ieq0018.tif "/> -haemolytic): Endocarditis, UTIs, intra-abdominal infections, wound infection. Gram-positive bacilli Corynebacterium diphtheriae : Diphtheria. Bacillus anthracis (spore-forming): Cutaneous anthrax, pulmonary anthrax, and gastrointestinal anthrax. Bacillus cereus (spore-forming): Gastrointestinal poisoning which self-terminates in 24 h. Clostridium perfringens (spore-forming anaerobes): Gas gangrene. Clostridium difficile (spore-forming anaerobes): Pseudomembranous colitis. Clostridium botulinum (spore-forming anaerobes): Botulism. Clostridium tetani (spore-forming anaerobes): Tetanus. Listeria monocytogenes : Meningitis in neonates and elderly. Propionibacterium : Skin problems, such as acne vulgaris.
2025-09-01 | Current Understanding on the Biology of <i>Bacillus Anthracis</i> and Its Pathophysiology: A Critical Appraisal
Bacillus anthracis, the causative agent of anthrax, is a Gram-positive bacterium that poses serious concerns for public health and biodefense and capable of forming resilient spores enables prolonged environmental survival, and it can infect hosts through cutaneous, inhalational, gastrointestinal or injection routes. The pathogenicity of bacteria is primarily attributed to its poly-D-glutamic acid capsule and a tripartite exotoxin complex consisting of protective antigen, edema factor and lethal factor, which collectively facilitate immune evasion and systemic spread. While herbivores are particularly vulnerable, all warm-blooded animals, including humans, are susceptible to infection. Natural outbreaks are frequently associated with contaminated soil, making geographic and ecological surveillance essential in endemic regions. Vaccination, particularly with protective antigen (PA)-based vaccines, is the most effective preventive strategy, although challenges in vaccine tolerance and accessibility remain. Recent advances in molecular epidemiology and genomic sequencing have enhanced the tracking of outbreak sources and strain variation. Prompt administration of antimicrobial therapy and monoclonal antibody use are critical for successful treatment. Additionally, proper carcass disposal, environmental decontamination, and active surveillance are crucial for breaking the transmission cycle and managing outbreaks. Understanding the molecular pathogenesis, host susceptibility and immunological responses is essential for advancing diagnostics, therapeutics and control measures.
2023-03-21 | Efficacy of ANTHRASIL (Anthrax Immune Globulin Intravenous (Human)) in rabbit and nonhuman primate models of inhalational anthrax: Data supporting approval under animal rule.
To meet the requirements of the Animal Rule, the efficacy of monotherapy with ANTHRASIL® (Anthrax Immune Globulin Intravenous (Human)) for inhalational anthrax was evaluated in blinded studies using rabbit and nonhuman primate models. Animals in both studies were randomized to treatment groups exposed to ~ 200 LD50 Bacillus anthracis (Ames strain) spores by the aerosol route to induce inhalational anthrax. Rabbits (N = 50/group) were treated with either 15 U/kg ANTHRASIL or a volume-matching dose of IGIV after disease onset as determined by the detection of bacterial toxin in the blood. At the end of the study, survival rates were 2% (1 of 48) in the IGIV control group, and 26% (13 of 50) in the ANTHRASIL-treated group (p = 0.0009). Similarly, ANTHRASIL was effective in cynomolgus monkeys (N = 16/group) when administered therapeutically after the onset of toxemia, with 6% survival in the IGIV control and a dose-related increase in survival of 36%, 43%, and 70% with 7.5, 15 or 30 U/kg doses of ANTHRASIL, respectively. These studies formed the basis for approval of ANTHRASIL by FDA under the Animal Rule.
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2024-07-20 | Flexible RNA aptamers as inhibitors of Bacillus anthracis ribosomal protein S8: Insights from molecular dynamics simulations.
Bacillus anthracis, the causative agent of anthrax, poses a substantial threat to public health and national security, and is recognized as a potential bioweapon due to its capacity to form resilient spores with enduring viability. Inhalation or ingestion of even minute quantities of aerosolized spores can lead to widespread illness and fatalities, underscoring the formidable lethality of the bacterium. With an untreated mortality rate of 100%, Bacillus anthracis is a disconcerting candidate for bioterrorism. In response to this critical scenario, we employed state-of-the-art computational tools to conceive and characterize flexible RNA aptamer therapeutics tailored for anthrax. The foundational structure of the flexible RNA aptamers was designed by removing the C2'-C3' in each nucleotide unit. Leveraging the crystal structure of Bacillus anthracis ribosomal protein S8 complexed with an RNA aptamer, we explored the structural, dynamic, and energetic aspects of the modified RNA aptamer - S8 protein complexes through extensive all-atom explicit-solvent molecular dynamics simulations (400 ns, 3 replicas each), followed by drawing comparisons to the control system. Our findings demonstrate the enhanced binding competencies of the flexible RNA aptamers to the S8 protein via better shape complementarity and improved H-bond network compared to the control RNA aptamer. This research offers valuable insights into the development of RNA aptamer therapeutics targeting Bacillus anthracis, paving the way for innovative strategies to mitigate the impact of this formidable pathogen.
2024-04-27 | Investigating the Influence of ANTXR2 Gene Mutations on Protective Antigen Binding for Heightened Anthrax Resistance.
Bacillus anthracis is the bacterium responsible for causing the zoonotic disease called anthrax. The disease presents itself in different forms like gastrointestinal, inhalation, and cutaneous. Bacterial spores are tremendously adaptable, can persist for extended periods and occasionally endanger human health. The Anthrax Toxin Receptor-2 (ANTXR2) gene acts as membrane receptor and facilitates the entry of the anthrax toxin into host cells. Additionally, mutations in the ANTXR2 gene have been linked to various autoimmune diseases, including Hyaline Fibromatosis Syndrome (HFS), Ankylosing Spondylitis (AS), Juvenile Hyaline Fibromatosis (JHF), and Infantile Systemic Hyalinosis (ISH). This study delves into the genetic landscape of ANTXR2, aiming to comprehend its associations with diverse disorders, elucidate the impacts of its mutations, and pinpoint minimal non-pathogenic mutations capable of reducing the binding affinity of the ANTXR2 gene with the protective antigen. Recognizing the pivotal role of single-nucleotide polymorphisms (SNPs) in shaping genetic diversity, we conducted computational analyses to discern highly deleterious and tolerated non-synonymous SNPs (nsSNPs) in the ANTXR2 gene. The Mutpred2 server determined that the Arg465Trp alteration in the ANTXR2 gene leads to altered DNA binding (p = 0.22) with a probability of a deleterious mutation of 0.808; notably, among the identified deleterious SNPs, rs368288611 (Arg465Trp) stands out due to its significant impact on altering the DNA-binding ability of ANTXR2. We propose these SNPs as potential candidates for hypertension linked to the ANTXR2 gene, which is implicated in blood pressure regulation. Noteworthy among the tolerated substitutions is rs200536829 (Ala33Ser), recognized as less pathogenic; this highlights its potential as a valuable biomarker, potentially reducing side effects on the host while also reducing binding with the protective antigen protein. Investigating these SNPs holds the potential to correlate with several autoimmune disorders and mitigate the impact of anthrax disease in humans.
2016-08-01 | Gene control of tyrosine kinase TIE2 and vascular manifestations of infections.
Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.
2014-04-18 | Targeted Silencing of Anthrax Toxin Receptors Protects against Anthrax Toxins
Anthrax spores can be aerosolized and dispersed as a bioweapon. Current postexposure treatments are inadequate at later stages of infection, when high levels of anthrax toxins are present. Anthrax toxins enter cells via two identified anthrax toxin receptors: tumor endothelial marker 8 (TEM8) and capillary morphogenesis protein 2 (CMG2). We hypothesized that host cells would be protected from anthrax toxins if anthrax toxin receptor expression was effectively silenced using RNA interference (RNAi) technology. Thus, anthrax toxin receptors in mouse and human macrophages were silenced using targeted siRNAs or blocked with specific antibody prior to challenge with anthrax lethal toxin. Viability assays were used to assess protection in macrophages treated with specific siRNA or antibody as compared with untreated cells. Silencing CMG2 using targeted siRNAs provided almost complete protection against anthrax lethal toxin-induced cytotoxicity and death in murine and human macrophages. The same results were obtained by prebinding cells with specific antibody prior to treatment with anthrax lethal toxin. In addition, TEM8-targeted siRNAs also offered significant protection against lethal toxin in human macrophage-like cells. Furthermore, silencing CMG2, TEM8, or both receptors in combination was also protective against MEK2 cleavage by lethal toxin or adenylyl cyclase activity by edema toxin in human kidney cells. Thus, anthrax toxin receptor-targeted RNAi has the potential to be developed as a life-saving, postexposure therapy against anthrax. Anthrax spores can be aerosolized and dispersed as a bioweapon. Current postexposure treatments are inadequate at later stages of infection, when high levels of anthrax toxins are present. Anthrax toxins enter cells via two identified anthrax toxin receptors: tumor endothelial marker 8 (TEM8) and capillary morphogenesis protein 2 (CMG2). We hypothesized that host cells would be protected from anthrax toxins if anthrax toxin receptor expression was effectively silenced using RNA interference (RNAi) technology. Thus, anthrax toxin receptors in mouse and human macrophages were silenced using targeted siRNAs or blocked with specific antibody prior to challenge with anthrax lethal toxin. Viability assays were used to assess protection in macrophages treated with specific siRNA or antibody as compared with untreated cells. Silencing CMG2 using targeted siRNAs provided almost complete protection against anthrax lethal toxin-induced cytotoxicity and death in murine and human macrophages. The same results were obtained by prebinding cells with specific antibody prior to treatment with anthrax lethal toxin. In addition, TEM8-targeted siRNAs also offered significant protection against lethal toxin in human macrophage-like cells. Furthermore, silencing CMG2, TEM8, or both receptors in combination was also protective against MEK2 cleavage by lethal toxin or adenylyl cyclase activity by edema toxin in human kidney cells. Thus, anthrax toxin receptor-targeted RNAi has the potential to be developed as a life-saving, postexposure therapy against anthrax.
2013-09-18 | Rapid targeted gene disruption in Bacillus anthracis
Abstract Background Anthrax is a zoonotic disease recognized to affect herbivores since Biblical times and has the widest range of susceptible host species of any known pathogen. The ease with which the bacterium can be weaponized and its recent deliberate use as an agent of terror, have highlighted the importance of gaining a deeper understanding and effective countermeasures for this important pathogen. High quality sequence data has opened the possibility of systematic dissection of how genes distributed on both the bacterial chromosome and associated plasmids have made it such a successful pathogen. However, low transformation efficiency and relatively few genetic tools for chromosomal manipulation have hampered full interrogation of its genome. Results Group II introns have been developed into an efficient tool for site-specific gene inactivation in several organisms. We have adapted group II intron targeting technology for application in Bacillus anthracis and generated vectors that permit gene inactivation through group II intron insertion. The vectors developed permit screening for the desired insertion through PCR or direct selection of intron insertions using a selection scheme that activates a kanamycin resistance marker upon successful intron insertion. Conclusions The design and vector construction described here provides a useful tool for high throughput experimental interrogation of the Bacillus anthracis genome and will benefit efforts to develop improved vaccines and therapeutics.
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Drug Discovery Landscape
17 orphan drug designations for Inhalational anthrax, including 5 approved therapies.
17 orphan drug designations for Inhalational anthrax, including 5 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
omadacycline p-toluenesulfonate | small molecules | FDA | 2026-04-26 | — | Paratek Pharmaceuticals, Inc. |
Anthrax Vaccine Adsorbed, Adjuvanted [Cyfendus] | vaccines | FDA | 2021-08-19 | 2023-07-20 | Emergent Product Development Gaithersburg, Inc. |
Obiltoxaximab [Nyxthracis] | antibodies | EMA | 2018-08-24 | — | Sfl Pharmaceuticals Deutschland GmbH |
L-alanoyl-D-glutamate endopeptidase from Bacillus-infected bacteriophages | proteins | FDA | 2018-06-21 | — | iNtRON Biotechnology, Inc. |
Raxibacumab | antibodies | EMA | 2014-10-15 | — | Emergent Operations Ireland Limited |
Anthrax Vaccine Adsorbed [BioThrax] | vaccines | FDA | 2014-04-11 | 2015-11-23 | Emergent BioDefense Operations Lansing LLC |
Human anthrax monoclonal antibody [AVP-21D9] | antibodies | EMA | 2011-08-05 | — | Emergent Sales and Marketing Germany GmbH |
Human anthrax monoclonal antibody [AVP-21D9] | antibodies | EMA | 2011-04-15 | — | Emergent Sales and Marketing Germany GmbH |
human monoclonal anti-PA antibody | antibodies | FDA | 2010-10-21 | — | Emergent Product Development Gaithersburg, Inc. |
Human anthrax immunoglobulin [Anthrivig] | antibodies | EMA | 2009-11-09 | — | Emergent Sales and Marketing Germany GmbH |
Human anthrax immunoglobulin | antibodies | EMA | 2009-11-05 | — | Emergent Sales and Marketing Germany GmbH |
anthrax immune globulin | antibodies | FDA | 2009-09-03 | — | Emergent Biosolutions, Inc. |
anthrax immune globulin (human) | antibodies | FDA | 2008-07-29 | 2015-03-24 | Cangene Corp. - Emergent Biosolutions |
cethromycin | small molecules | FDA | 2007-02-28 | — | Advanced LIfe Sciences, Inc. |
obiltoxaximab [Anthim] | antibodies | FDA | 2006-06-09 | 2016-03-18 | Elusys Therapeutics, Inc. |
Recombinant fully human monoclonal antibody to anthrax protective antigen | antibodies | FDA | 2006-02-16 | — | Altimmune, Inc. |
raxibacumab [ABthraxTM] | antibodies | FDA | 2003-11-12 | 2012-12-14 | Human Genome Sciences, Inc. |
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