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Carprofen elicits pleiotropic mechanisms of bactericidal action with the potential to reverse antimicrobial drug resistance in tuberculosis

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Version 2 2023-06-07, 08:50
Version 1 2023-06-07, 07:24
journal contribution
posted on 2023-06-07, 08:50 authored by Arundhati Maitra, Dimitrios Evangelopoulos, Alina Chrzastek, Liam T Martin, Aidan Hanrath, Ellie Chapman, Helen C Hailes, Marc Lipman, Timothy D McHugh, Simon WaddellSimon Waddell, Sanjib Bhakta
Background The rise of antimicrobial drug resistance in Mycobacterium tuberculosis coupled with the shortage of new antibiotics has elevated TB to a major global health priority. Repurposing drugs developed or used for other conditions has gained special attention in the current scenario of accelerated drug development for several global infectious diseases. In a similar effort, previous studies revealed that carprofen, a non-steroidal anti-inflammatory drug, selectively inhibited the growth of replicating, non-replicating and MDR clinical isolates of M. tuberculosis. Objectives We aimed to reveal the whole-cell phenotypic and transcriptomic effects of carprofen in mycobacteria. Methods Integrative molecular and microbiological approaches such as resazurin microtitre plate assay, high-throughput spot-culture growth inhibition assay, whole-cell efflux inhibition, biofilm inhibition and microarray analyses were performed. Analogues of carprofen were also synthesized and assessed for their antimycobacterial activity. Results Carprofen was found to be a bactericidal drug that inhibited mycobacterial drug efflux mechanisms. It also restricted mycobacterial biofilm growth. Transcriptome profiling revealed that carprofen likely acts by targeting respiration through the disruption of membrane potential. The pleiotropic nature of carprofen’s anti-TB action may explain why spontaneous drug-resistant mutants could not be isolated in practice. Conclusions This immunomodulatory drug and its chemical analogues have the potential to reverse TB antimicrobial drug resistance, offering a swift path to clinical trials of novel TB drug combinations.

History

Publication status

  • Published

File Version

  • Published version

Journal

Journal of Antimicrobial Chemotherapy

ISSN

0305-7453

Publisher

Oxford University Press

Page range

1-8

Department affiliated with

  • Global Health and Infection Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2020-07-02

First Open Access (FOA) Date

2020-08-19

First Compliant Deposit (FCD) Date

2020-07-02

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