Mechanisms of Resistance Associated with the Inhibition of the Dehydration Step of Type II Fatty Acid Synthase in Mycobacterium tuberculosis.

ABSTRACT: Isoxyl (ISO) and thiacetazone (TAC) are two antitubercular prodrugs that abolish mycolic acid biosynthesis and kill Mycobacterium tuberculosis (Mtb) through the inhibition of the essential type II fatty acid synthase (FAS-II) dehydratase HadAB. While mutations preventing ISO and TAC either from being converted to their active form or from covalently modifying their target are the most frequent spontaneous mutations associated with high-level resistance to both drugs, the molecular mechanisms underlying the high-level ISO and TAC resistance of Mtb strains harboring missense mutations in the second, nonessential, FAS-II dehydratase HadBC have remained unexplained. Using a combination of genetic, biochemical, and biophysical approaches and molecular dynamics simulation, w

SUBMITTER: Grzegorzewicz AE 

PROVIDER: S-EPMC8078599 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature