Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from <i>Mycobacterium tuberculosis</i> to overcome kanamycin resistance.

ABSTRACT: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a deadly bacterial disease. Drug-resistant strains of Mtb make eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by Mtb confers resistance to the second-line antibiotic kanamycin (KAN). Eis is an acetyltransferase that acetylates KAN, inactivating its antimicrobial function. Development of Eis inhibitors as KAN adjuvant therapeutics is an attractive path to forestall and overcome KAN resistance. We discovered that an antipsychotic drug, haloperidol (HPD, 1), was a potent Eis inhibitor with IC₅₀ = 0.39 ± 0.08 μM. We determined the crystal structure of the Eis-haloperidol (1) complex, which guided synthesis of 34 analogues

SUBMITTER: Punetha A 

PROVIDER: S-EPMC8597425 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature