Lack of Specificity of Phenotypic Screens for Inhibitors of the Mycobacterium tuberculosis FAS-II System.

Anna E Grzegorzewicz, Joël Lelièvre, Jorge Esquivias, Bhanupriya Angala, Jiuyu Liu, Richard E Lee, Michael R McNeil, Mary Jackson

Journal: Antimicrobial agents and chemotherapy 2021;65(1):e01914-20

PMID: 33139282

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Abstract

Phenotypic screening of inhibitors of the essential FAS-II dehydratase HadAB led to the identification of GSK3011724A, a compound previously reported to inhibit the condensation step of FAS-II. Whole-cell-based and cell-free assays confirmed the lack of activity of GSK3011724A against the dehydratase despite evidence of cross-resistance between GSK3011724A and HadAB inhibitors. The nature of the resistance mechanisms is suggestive of alterations in the FAS-II interactome reducing access of GSK3011724A to KasA.

Address: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.; Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.; Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.; Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA [email protected].

DOI: 10.1128/AAC.01914-20