Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis from <i>Mycobacterium tuberculosis</i>.

ABSTRACT: The enhanced intracellular survival (Eis) protein of Mycobacterium tuberculosis (Mtb) is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of Mtb, we designed and optimized structurally unique thieno[2,3-d]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy. We obtained 12 crystal structures of enzyme-inhibitor complexes, which guided our rational structure-based design of 72 thieno[2,3-d]pyrimidine analogues divided into three families. We evaluated the potency of these inhibitors in vitro as wel

SUBMITTER: Punetha A 

PROVIDER: S-EPMC7385556 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature