MptpB Inhibitor Improves the Action of Antibiotics against Mycobacterium tuberculosis and Nontuberculous Mycobacterium avium Infections
Rodríguez-Fernández, Pablo (University of Manchester)
Botella, Laure (The Francis Crick Institute (Londres, Regne Unit))
Cavet, Jennifer S. (University of Manchester)
Domínguez, José (Institut Germans Trias i Pujol)
Gutierrez, Maximiliano G. (The Francis Crick Institute)
Suckling, Colin J. (University of Strathclyde)
Scott, Fraser J. (University of Strathclyde (Glasgow, Regne Unit))
Tabernero, Lydia (University of Manchester)
Universitat Autònoma de Barcelona

Date:	2023
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.
Grants:	Instituto de Salud Carlos III PI19/01408 European Commission 823854
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	MptpB ; Mycobacterium tuberculosis ; Mycobacterium avium ; Combination of antibiotics ; LAMP-1 lysosomal marker ; Galleria mellonella
Published in:	ACS infectious diseases, Vol. 10 (december 2023) , p. 170-183, ISSN 2373-8227

DOI: 10.1021/acsinfecdis.3c00446
PMID: 38085851

14 p, 6.2 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles