Affiliation:
1. JMI Laboratories, North Liberty, Iowa, USA
2. GSK, Collegeville, Pennsylvania, USA
Abstract
ABSTRACT
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 MIC
90
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.
Funder
GlaxoSmithKline
HHS | Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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