Open AccessLack of Specificity of Phenotypic Screens for Inhibitors of the Mycobacterium tuberculosis FAS-II System
Author(s) -
Anna E. Grzegorzewicz,
Joël Lelièvre,
Jorge Esquivias,
Bhanupriya Angala,
Jiuyu Liu,
Richard Lee,
Michael McNeil,
Mary Jackson
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01914-20
Subject(s) - mycobacterium tuberculosis , dehydratase , phenotype , biology , tuberculosis , microbiology and biotechnology , virology , genetics , enzyme , medicine , biochemistry , gene , pathology
Phenotypic screening of inhibitors of the essential Mycobacterium tuberculosis 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.