Cathelicidin peptide rescues <i>G. mellonella</i> infected with <i>B. anthracis</i>

Blower, Ryan J.; Попов, Сергей Витальевич; Hoek, Monique L. van

doi:10.1080/21505594.2017.1293227

Cited by 15 publications

(16 citation statements)

References 42 publications

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“…mellonella infection model suitable for our inferences because it has been used to characterize major B . anthracis Sterne virulence factors following vegetative cell challenge [ 69 ] and for down-selecting antibacterial peptides active against Ba for future use in an animal model [ 70 ]. It also allows challenge of desired animal numbers inexpensively and humanely while serving as an accurate innate immune animal model.…”

Section: Resultsmentioning

confidence: 99%

Convergent evolution of diverse Bacillus anthracis outbreak strains toward altered surface oligosaccharides that modulate anthrax pathogenesis

et al. 2020

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Bacillus anthracis, a spore-forming gram-positive bacterium, causes anthrax. The external surface of the exosporium is coated with glycosylated proteins. The sugar additions are capped with the unique monosaccharide anthrose. The West African Group (WAG) B. anthracis have mutations rendering them anthrose deficient. Through genome sequencing, we identified 2 different large chromosomal deletions within the anthrose biosynthetic operon of B. anthracis strains from Chile and Poland. In silico analysis identified an anthrose-deficient strain in the anthrax outbreak among European heroin users. Anthrose-deficient strains are no longer restricted to West Africa so the role of anthrose in physiology and pathogenesis was investigated in B. anthracis Sterne. Loss of anthrose delayed spore germination and enhanced sporulation. Spores without anthrose were phagocytized at higher rates than spores with anthrose, indicating that anthrose may serve an antiphagocytic function on the spore surface. The anthrose mutant had half the LD50 and decreased time to death (TTD) of wild type and complement B. anthracis Sterne in the A/J mouse model. Following infection, anthrose mutant bacteria were more abundant in the spleen, indicating enhanced dissemination of Sterne anthrose mutant. At low sample sizes in the A/J mouse model, the mortality of ΔantC-infected mice challenged by intranasal or subcutaneous routes was 20% greater than wild type. Competitive index (CI) studies indicated that spores without anthrose disseminated to organs more extensively than a complemented mutant. Death process modeling using mouse mortality dynamics suggested that larger sample sizes would lead to significantly higher deaths in anthrose-negative infected animals. The model was tested by infecting Galleria mellonella with spores and confirmed the anthrose mutant was significantly more lethal. Vaccination studies in the A/J mouse model showed that the human vaccine protected against high-dose challenges of the nonencapsulated Sterne-based anthrose mutant. This work begins to identify the physiologic and pathogenic consequences of convergent anthrose mutations in B. anthracis.

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Section: Resultsmentioning

confidence: 99%

Convergent evolution of diverse Bacillus anthracis outbreak strains toward altered surface oligosaccharides that modulate anthrax pathogenesis

et al. 2020

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“…Bacterial endospores are metabolically dormant and environmentally resistant and are capable of surviving antibiotic exposure, extremes of temperature, desiccation and ionizing radiation (Higgins and Dworkin, 2012 ). The cathelicidin family AMP PG-1, BMAP28, and LL-37 demonstrated sporicidal activity against B. anthracis spores in the low mg/L range, whereas SMAP-29, CAP-18 were not effective and NA-CATH and mCRAMP demonstrated activity only at high concentrations (1,000 mg/L) (Blower et al, 2018 ). The AMP chrysophin-3 also demonstrated sporicidal activity vs. B. anthracis (Pinzon-Arango et al, 2013 ) and activity of PG-1 vs. spores of B. anthracis had been previously reported (Lisanby et al, 2008 ).…”

Section: Antimicrobial Susceptibility Testing Of Ampmentioning

confidence: 99%

Antimicrobial Susceptibility Testing of Antimicrobial Peptides to Better Predict Efficacy

Mercer

Torres

Duay

et al. 2020

Front. Cell. Infect. Microbiol.

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During the development of antimicrobial peptides (AMP) as potential therapeutics, antimicrobial susceptibility testing (AST) stands as an essential part of the process in identification and optimisation of candidate AMP. Standard methods for AST, developed almost 60 years ago for testing conventional antibiotics, are not necessarily fit for purpose when it comes to determining the susceptibility of microorganisms to AMP. Without careful consideration of the parameters comprising AST there is a risk of failing to identify novel antimicrobials at a time when antimicrobial resistance (AMR) is leading the planet toward a post-antibiotic era. More physiologically/clinically relevant AST will allow better determination of the preclinical activity of drug candidates and allow the identification of lead compounds. An important consideration is the efficacy of AMP in biological matrices replicating sites of infection, e.g., blood/plasma/serum, lung bronchiolar lavage fluid/sputum, urine, biofilms, etc., as this will likely be more predictive of clinical efficacy. Additionally, specific AST for different target microorganisms may help to better predict efficacy of AMP in specific infections. In this manuscript, we describe what we believe are the key considerations for AST of AMP and hope that this information can better guide the preclinical development of AMP toward becoming a new generation of urgently needed antimicrobials.

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“…Galleria mellonella , the greater wax moth, has been proposed as an alternative model that is relatively easy to obtain and has a system of antimicrobial protection similar to that of mammals. These factors make larvae of G. mellonella a model of infection for various pathogenic microorganisms [2, 32, 48, 49]. G. mellonella has been previously used as an infection model for in vivo effect of antimicrobial peptides and antibiotics against Francisella spp.…”

Section: Resultsmentioning

confidence: 99%

Intraperitoneal treatment with antimicrobial peptide rescues mice from a pulmonaryFrancisellainfection

Hoek

Kaushal

Bishop

et al. 2019

Preprint

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7Our long-term goal is to identify new antimicrobial peptides that might be effective 8 against pneumonic Francisella infection in mice. Previously, our group searched the peptidome 9 of the American alligator for novel cationic antimicrobial peptides and identified a naturally-10 occurring C-terminal fragment of apolipoprotein C-1, which we called Apo6. This peptide was 11 found to have antibacterial activity against the ESKAPE pathogens, including those exhibiting 12 multi-drug resistance. In this work, we tested Apo6 and synthetic derivatives for antibacterial 13 activity against Francisella tularensis including the virulent strain F. tularensis SchuS4.14 Francisella is inherently highly resistant to the cyclic peptide polymyxin antibiotics and beta-15 lactam antibiotics. We found that our synthetic peptide derivatives (called GATR peptides), 16 designed with increased hydrophobicity and charge, had generally stronger in vitro antimicrobial 17 activity against Francisella than the parent peptide Apo6. The GATR peptides had a greater 18 effect on the bacterial membrane than the Apo6 peptide and were able to bind Francisella LPS, 19 suggesting their mechanism of action against Francisella. Cytotoxicity experiments showed low 20 cytotoxicity for most of the GATR peptides, and whole organism toxicity studies in the 21 waxworm allowed us to down-select to two our lead peptides, GATR-3 and GATR-6. These 22 peptides were tested in a murine pulmonary tularemia model. We found that the GATR-3 peptide 23 rescued 50-60% of mice from lethal tularemia infection when administered systemically through 24 2 the intraperitoneal route. This peptide is a candidate for further pre-clinical studies for a potential 25 peptide-based approach to tularemia. 26

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Cathelicidin peptide rescues G. mellonella infected with B. anthracis

Cited by 15 publications

References 42 publications

Convergent evolution of diverse Bacillus anthracis outbreak strains toward altered surface oligosaccharides that modulate anthrax pathogenesis

Convergent evolution of diverse Bacillus anthracis outbreak strains toward altered surface oligosaccharides that modulate anthrax pathogenesis

Antimicrobial Susceptibility Testing of Antimicrobial Peptides to Better Predict Efficacy

Intraperitoneal treatment with antimicrobial peptide rescues mice from a pulmonaryFrancisellainfection

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