Contribution of direct InhA inhibitors to novel drug regimens in a mouse model of tuberculosis.

Autor:	Encinas L; Global Health Medicines R&D, GSK, Tres Cantos, Madrid, Spain., Li S-Y; Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland, USA., Rullas-Trincado J; Global Health Medicines R&D, GSK, Tres Cantos, Madrid, Spain., Tasneen R; Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland, USA., Tyagi S; Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland, USA., Soni H; Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland, USA., Garcia-Perez A; Discovery DMPK, GSK, Tres Cantos, Madrid, Spain., Lee J; Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland, USA., González Del Río R; Global Health Medicines R&D, GSK, Tres Cantos, Madrid, Spain., De Mercado J; Discovery DMPK, GSK, Tres Cantos, Madrid, Spain., Sousa V; Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland, USA., Sosič I; Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia., Gobec S; Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia., Mendoza-Losana A; Global Health Medicines R&D, GSK, Tres Cantos, Madrid, Spain., Converse PJ; Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland, USA., Mdluli K; TB Alliance: Global Alliance for Tuberculosis Drug Development, New York, New York, USA., Fotouhi N; TB Alliance: Global Alliance for Tuberculosis Drug Development, New York, New York, USA., Barros-Aguirre D; Global Health Medicines R&D, GSK, Tres Cantos, Madrid, Spain., Nuermberger EL; Center for Tuberculosis Research, Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Nov 06; Vol. 68 (11), pp. e0035724. Date of Electronic Publication: 2024 Sep 30.
DOI:	10.1128/aac.00357-24
Abstrakt:	Isoniazid is an important first-line medicine to treat tuberculosis (TB). Isoniazid resistance increases the risk of poor treatment outcomes and development of multidrug resistance, and is driven primarily by mutations involving katG , encoding the prodrug-activating enzyme, rather than its validated target, InhA. The chemical tractability of InhA has fostered efforts to discover direct inhibitors of InhA (DIIs). In this study, we bridge the gap in understanding the potential contribution of DIIs to novel combination regimens and demonstrate a clear distinction of DIIs, like GSK693 and the newly described GSK138, from isoniazid, based on activity against clinical isolates and contribution to novel drug regimens. The results suggest that DIIs, specifically GSK138 and GSK693, could be promising partners in novel drug regimens, including those used against isoniazid-resistant TB, potentially enhancing their efficacy and/or preventing the selection of resistant mutants and supporting the continued exploration of InhA as a promising target for TB drug development. Competing Interests: L.E., J.R.-T., A.G.-P., R.G.D.R., and D.B.-A. are employees of, and shareholders in, GSK. A.M.-L. holds GSK stock and has patents issued during his employment at GSK. J.D.M. and V.S. are employees of GSK. The other authors declare no conflict of interest.
Databáze:	MEDLINE
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