Development of antibacterial compounds that constrain evolutionary pathways to resistance

Antibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here, we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and tr...

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Autores principales:	Yanmin Zhang, Sourav Chowdhury, João V Rodrigues, Eugene Shakhnovich
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	antibiotic resistance evolution drug computational modelling dihydrofolate reductase Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7a642803bf564a9caf6ec50bfa00229a
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spelling	oai:doaj.org-article:7a642803bf564a9caf6ec50bfa00229a2021-11-25T14:31:36ZDevelopment of antibacterial compounds that constrain evolutionary pathways to resistance10.7554/eLife.645182050-084Xe64518https://doaj.org/article/7a642803bf564a9caf6ec50bfa00229a2021-07-01T00:00:00Zhttps://elifesciences.org/articles/64518https://doaj.org/toc/2050-084XAntibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here, we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants of E. coli dihydrofolate reductase (DHFR). We identified a novel compound (CD15-3) that inhibits WT DHFR and its TMP resistant variants L28R, P21L and A26T with IC50 50–75 µM against WT and TMP-resistant strains. Resistance to CD15-3 was dramatically delayed compared to TMP in in vitro evolution. Whole genome sequencing of CD15-3-resistant strains showed no mutations in the target folA locus. Rather, gene duplication of several efflux pumps gave rise to weak (about twofold increase in IC50) resistance against CD15-3. Altogether, our results demonstrate the promise of strategy to develop evolution drugs - compounds which constrain evolutionary escape routes in pathogens.Yanmin ZhangSourav ChowdhuryJoão V RodriguesEugene ShakhnovicheLife Sciences Publications Ltdarticleantibiotic resistanceevolution drugcomputational modellingdihydrofolate reductaseMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antibiotic resistance evolution drug computational modelling dihydrofolate reductase Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	antibiotic resistance evolution drug computational modelling dihydrofolate reductase Medicine R Science Q Biology (General) QH301-705.5 Yanmin Zhang Sourav Chowdhury João V Rodrigues Eugene Shakhnovich Development of antibacterial compounds that constrain evolutionary pathways to resistance
description	Antibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here, we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants of E. coli dihydrofolate reductase (DHFR). We identified a novel compound (CD15-3) that inhibits WT DHFR and its TMP resistant variants L28R, P21L and A26T with IC50 50–75 µM against WT and TMP-resistant strains. Resistance to CD15-3 was dramatically delayed compared to TMP in in vitro evolution. Whole genome sequencing of CD15-3-resistant strains showed no mutations in the target folA locus. Rather, gene duplication of several efflux pumps gave rise to weak (about twofold increase in IC50) resistance against CD15-3. Altogether, our results demonstrate the promise of strategy to develop evolution drugs - compounds which constrain evolutionary escape routes in pathogens.
format	article
author	Yanmin Zhang Sourav Chowdhury João V Rodrigues Eugene Shakhnovich
author_facet	Yanmin Zhang Sourav Chowdhury João V Rodrigues Eugene Shakhnovich
author_sort	Yanmin Zhang
title	Development of antibacterial compounds that constrain evolutionary pathways to resistance
title_short	Development of antibacterial compounds that constrain evolutionary pathways to resistance
title_full	Development of antibacterial compounds that constrain evolutionary pathways to resistance
title_fullStr	Development of antibacterial compounds that constrain evolutionary pathways to resistance
title_full_unstemmed	Development of antibacterial compounds that constrain evolutionary pathways to resistance
title_sort	development of antibacterial compounds that constrain evolutionary pathways to resistance
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/7a642803bf564a9caf6ec50bfa00229a
work_keys_str_mv	AT yanminzhang developmentofantibacterialcompoundsthatconstrainevolutionarypathwaystoresistance AT souravchowdhury developmentofantibacterialcompoundsthatconstrainevolutionarypathwaystoresistance AT joaovrodrigues developmentofantibacterialcompoundsthatconstrainevolutionarypathwaystoresistance AT eugeneshakhnovich developmentofantibacterialcompoundsthatconstrainevolutionarypathwaystoresistance
_version_	1718413387578212352

Development of antibacterial compounds that constrain evolutionary pathways to resistance

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