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In Vitro Potency and Spectrum of the Novel Polymyxin MRX-8 Tested against Clinical Isolates of Gram-Negative Bacteria.

ABSTRACT: The polymyxins display excellent in vitro antimicrobial activity against most Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii isolates, but their clinical utility has been limited because of class-specific toxicity problems. Therefore, new polymyxin analogs with improved safety properties are needed to combat serious infections caused by resistant Gram-negative pathogens. MRX-8 is a novel polymyxin B analog that displays reduced toxicity in in vitro and animal assays and is currently being evaluated in a phase 1 clinical trial. In this nonclinical study, the in vitro potency and spectrum of MRX-8 and comparators were evaluated against a large set of Gram-negative clinical isolates collected in the United States in 2017 to 2020. MRX-8, colistin, and polymyxin B exhibited nearly identical antimicrobial activities against the Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii isolate sets. MRX-8 MIC₅₀ and MIC₉₀ values were 0.12 and 0.25 mg/L, respectively, for the set of Enterobacterales isolates not intrinsically resistant to colistin and 0.5 and 1 mg/L, respectively, against both the A. baumannii and P. aeruginosa isolate sets. All three polymyxin-class compounds retained activity against meropenem-resistant and multidrug-resistant isolate subsets but were inactive against isolates displaying acquired or intrinsic resistance to polymyxins. These results support the continued development of MRX-8 to treat serious Gram-negative infections.

SUBMITTER: Duncan LR

PROVIDER: S-EPMC9112888 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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In Vitro Potency and Spectrum of the Novel Polymyxin MRX-8 Tested against Clinical Isolates of Gram-Negative Bacteria.

Duncan Leonard R LR Wang Wen W Sader Helio S HS

Antimicrobial agents and chemotherapy 20220427 5

The polymyxins display excellent in vitro antimicrobial activity against most Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii isolates, but their clinical utility has been limited because of class-specific toxicity problems. Therefore, new polymyxin analogs with improved safety properties are needed to combat serious infections caused by resistant Gram-negative pathogens. MRX-8 is a novel polymyxin B analog that displays reduced toxicity in in vitro and ...[more]

PMID: 35475635

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Project description:Gepotidacin is a first-in-class, novel triazaacenaphthylene antibiotic that inhibits bacterial DNA replication and has in vitro activity against susceptible and drug-resistant pathogens. Reference in vitro methods were used to investigate the MICs and minimum bactericidal concentrations (MBCs) of gepotidacin and comparator agents for Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli Gepotidacin in vitro activity was also evaluated by using time-kill kinetics and broth microdilution checkerboard methods for synergy testing and for postantibiotic and subinhibitory effects. The MIC90 of gepotidacin for 50 S. aureus (including methicillin-resistant S. aureus [MRSA]) and 50 S. pneumoniae (including penicillin-nonsusceptible) isolates was 0.5 μg/ml, and for E. coli (n = 25 isolates), it was 4 μg/ml. Gepotidacin was bactericidal against S. aureus, S. pneumoniae, and E. coli, with MBC/MIC ratios of ≤4 against 98, 98, and 88% of the isolates tested, respectively. Time-kill curves indicated that the bactericidal activity of gepotidacin was observed at 4× or 10× MIC at 24 h for all of the isolates. S. aureus regrowth was observed in the presence of gepotidacin, and the resulting gepotidacin MICs were 2- to 128-fold higher than the baseline gepotidacin MICs. Checkerboard analysis of gepotidacin combined with other antimicrobials demonstrated no occurrences of antagonism with agents from multiple antimicrobial classes. The most common interaction when testing gepotidacin was indifference (fractional inhibitory concentration index of >0.5 to ≤4; 82.7% for Gram-positive isolates and 82.6% for Gram-negative isolates). The postantibiotic effect (PAE) of gepotidacin was short when it was tested against S. aureus (≤0.6 h against MRSA and MSSA), and the PAE-sub-MIC effect (SME) was extended (>8 h; three isolates at 0.5× MIC). The PAE of levofloxacin was modest (0.0 to 2.4 h), and the PAE-SME observed varied from 1.2 to >9 h at 0.5× MIC. These in vitro data indicate that gepotidacin is a bactericidal agent that exhibits a modest PAE and an extended PAE-SME against Gram-positive and -negative bacteria and merits further study for potential use in treating infections caused by these pathogens.

Dataset Information

In Vitro Potency and Spectrum of the Novel Polymyxin MRX-8 Tested against Clinical Isolates of Gram-Negative Bacteria.

Publications

<i>In Vitro</i> Potency and Spectrum of the Novel Polymyxin MRX-8 Tested against Clinical Isolates of Gram-Negative Bacteria.

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