In vitro activity of bedaquiline and imipenem against actively growing, nutrient-starved, and intracellular mycobacterium abscessus

Olumide Martins, Jin Lee, Amit Kaushik, Nicole C. Ammerman, Kelly E. Dooley, Eric L. Nuermberger*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Mycobacterium abscessus lung disease is difficult to treat due to intrinsic drug resistance and the persistence of drug-tolerant bacteria. Currently, the standard of care is a multidrug regimen with at least 3 active drugs, preferably including a β-lactam (imipenem or cefoxitin). These regimens are lengthy and toxic and have limited efficacy. The search for more efficacious regimens led us to evaluate bedaquiline, a diarylquinoline licensed for treatment of multidrug-resistant tuberculosis. We performed in vitro time-kill experiments to evaluate the activity of bedaquiline alone and in combination with the first-line drug imipenem against M. abscessus under various conditions. Against actively growing bacteria, bedaquiline was largely bacteriostatic and antagonized the bactericidal activity of imipenem. Contrarily, against nutrient-starved persisters, bedaquiline was bactericidal, while imipenem was not, and bedaquiline drove the activity of the combination. In an intracellular infection model, bedaquiline and imipenem had additive bactericidal effects. Correlations between ATP levels and the bactericidal activity of imipenem and its antagonism by bedaquiline were observed. Interestingly, the presence of Tween 80 in the media affected the activity of both drugs, enhancing the activity of imipenem and reducing that of bedaquiline. Overall, these results show that bedaquiline and imipenem interact differently depending on culture conditions. Previously reported antagonistic effects of bedaquiline on imipenem were limited to conditions with actively multiplying bacteria and/or the presence of Tween 80, whereas the combination was additive or indifferent against nutrient-starved and intracellular M. abscessus, where promising bactericidal activity of the combination suggests it may have a role in future treatment regimens.

Original languageEnglish
Article numbere01545-21
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number12
DOIs
Publication statusPublished - 17 Nov 2021

Bibliographical note

Funding Information:
This work was funded by the National Institutes of Health (R21-AI137814 to E.L.N.), the Cystic Fibrosis Foundation (E.L.N.), and by Genentech (research fellowship grant to O.M.). K.E.D. is supported by National Institutes of Health (K24AI150349).

Publisher Copyright:
Copyright © 2021 American Society for Microbiology. All Rights Reserved.

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