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. 2020 Dec;9(1):1388-1392.
doi: 10.1080/22221751.2020.1775498.

In vitro activity of the first-in-class triazaacenaphthylene gepotidacin alone and in combination with doxycycline against drug-resistant and -susceptible Mycoplasma genitalium

Jørgen Skov Jensen  1 , Christina Nørgaard  1 , Nicole Scangarella-Oman  2 , Magnus Unemo  3
Affiliations

In vitro activity of the first-in-class triazaacenaphthylene gepotidacin alone and in combination with doxycycline against drug-resistant and -susceptible Mycoplasma genitalium

Jørgen Skov Jensen et al. Emerg Microbes Infect. 2020 Dec.

Abstract

Mycoplasma genitalium has developed resistance to first-line azithromycin and second-line moxifloxacin. Third-line pristinamycin is only 75% effective. Gepotidacin, a novel triazaacenaphthylene topoisomerase II inhibitor, blocks bacterial DNA replication. We determined the in vitro activity of gepotidacin alone and in combination with doxycycline against a diverse collection of Mycoplasma genitalium isolates (n = 54). Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined by a Vero-cell culture method. Macrolide resistance was present in 31 (57%) isolates, fluoroquinolone resistance in 18 (33%) isolates, and 17 (31%) had dual resistance. Synergy testing was performed for gepotidacin and doxycycline by checkerboard analysis for two macrolide- and two dual-resistant isolates. Gepotidacin was active against all 54 M. genitalium isolates with median and modal MICs of 0.125 mg/L and MIC90 of 0.25 mg/L (range ≤0.016-0.5 mg/L). No difference in gepotidacin MIC between macrolide-resistant and -susceptible isolates (p = 0.24) or between fluoroquinolone-, dual-resistant and -susceptible isolates (p = 0.2) was demonstrated. Gepotidacin MBCs were available for 44 M. genitalium isolates with median MIC of 0.064 mg/L and median MBC of 0.125 mg/L. All isolates had ≤4-fold difference between MIC and MBC, suggesting bactericidal effect for gepotidacin. Checkerboard analysis indicated synergistic effect for gepotidacin in combination with doxycycline [fractional inhibitory concentration index (ΣFICI) of 0.5] for two isolates and additive/indifference (ΣFICI at 0.62 and 0.75) for two isolates. Gepotidacin warrants further evaluation in clinical treatment trials for M. genitalium. Combination therapy with doxycycline should be clinically studied to assess effect and potential protection against development and/or spread of gepotidacin resistance.

Keywords: Mycoplasma genitalium; antimicrobial resistance; combination therapy; gepotidacin; in-vitro susceptibility testing.

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Conflict of interest statement

JSJ has received speaker’s fee from Hologic, BD, SpeeDx, and Cepheid and serves scientific advisory board of Roche Molecular Systems, Abbott Molecular, Cepheid, and Nabriva. CHK and MU report no conflicts. NS-O is employed by GlaxoSmithKline.

Figures

Figure 1.
Figure 1.
Distribution of gepotidacin (GEP), azithromycin (AZM), moxifloxacin (MXF), and doxycycline (DOX) MICs for 54 Mycoplasma genitalium isolates as determined by a Vero-cell culture-based assay [21].
See this image and copyright information in PMC

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Grants and funding

GlaxoSmithKline provided antimicrobial compounds and supported this study. This project has been funded in whole or in part with Federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (BARDA), under OTA Agreement No. HHSO100201300011C. The funder had no influence on the interpretation of the results.