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

Pablo Rodríguez-Fernández, Laure Botella, Jennifer S. Cavet, Jose Domínguez, Maximiliano G. Gutierrez, Colin J. Suckling, Fraser J. Scott, Lydia Tabernero

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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.
Original languageEnglish
Pages (from-to)170–183
Number of pages14
JournalACS Infectious Diseases
Volume10
Issue number1
Early online date12 Dec 2023
DOIs
Publication statusPublished - 12 Jan 2024

Keywords

  • MptpB
  • mycobacterium tuberculosis
  • mycobacterium avium
  • combination of antibiotics
  • Galleria mellonella

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