MptpB inhibitor improves the action of antibiotics against mycobacterium tuberculosis and nontuberculous mycobacterium avium infections

Rodríguez-Fernández, Pablo and Botella, Laure and Cavet, Jennifer S. and Domínguez, Jose and Gutierrez, Maximiliano G. and Suckling, Colin J. and Scott, Fraser J. and Tabernero, Lydia (2024) MptpB inhibitor improves the action of antibiotics against mycobacterium tuberculosis and nontuberculous mycobacterium avium infections. ACS Infectious Diseases, 10 (1). 170–183. (https://doi.org/10.1021/acsinfecdis.3c00446)

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Abstract

ABSTRACT: Treatment of Mycobacterium tuberculosis and Mycobacterium avium infections requires multiple drugs for long time periods. Mycobacterium protein-tyrosine-phosphatase B (MptpB) is a key M. tuberculosis virulence factor that subverts host antimicrobial activity to promote intracellular survival. Inhibition of MptpB reduces the infection burden in vivo and offers new opportunities to improve current treatments. Here, we demonstrate that M. avium produces an MptpB orthologue and that the MptpB inhibitor C13 reduces the M. avium infection burden in macrophages. Combining C13 with the antibiotics rifampicin or bedaquiline showed an additive effect, reducing intracellular infection of both M. tuberculosis and M. avium by 50%, compared to monotreatment with antibiotics alone. This additive effect was not observed with pretomanid. Combining C13 with the minor groove-binding compounds S-MGB-362 and S-MGB-363 also reduced the M. tuberculosis intracellular burden. Similar additive effects of C13 and antibiotics were confirmed in vivo using Galleria mellonella infections. We demonstrate that the reduced mycobacterial burden in macrophages observed with C13 treatments is due to the increased trafficking to lysosomes.

ORCID iDs

Scott, Fraser J. ORCID: https://orcid.org/0000-0003-0229-3698

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• Item metadata

  Item type:	Article
  ID code:	87617
  Dates:	Date Event 12 January 2024 Published 12 December 2023 Published Online 28 November 2023 Accepted
  Subjects:	Science > Chemistry
  Department:	Faculty of Science > Pure and Applied Chemistry
  Depositing user:	Pure Administrator
  Date deposited:	13 Dec 2023 11:40
  Last modified:	14 Dec 2024 01:36
  URI:	https://strathprints.strath.ac.uk/id/eprint/87617