title: Discovery and Optimization of Two Eis Inhibitor Families as Kanamycin Adjuvants against Drug-ResistantM. tuberculosis.
abstract: Drug-resistant tuberculosis (TB) is a global threat and innovative approaches such as using adjuvants of anti-TB therapeutics are required to combat it. High-throughput screening yielded two lead scaffolds of inhibitors ofMycobacterium tuberculosis(Mtb) acetyltransferase Eis, whose upregulation causes resistance to the anti-TB drug kanamycin (KAN). Chemical optimization on these scaffolds resulted in potent Eis inhibitors. One compound restored the activity of KAN in a KAN-resistantMtbstrain. Model structures of Eis-inhibitor complexes explain the structure-activity relationship.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Atefeh
authors.initials: A
authors.lastname: Garzan
authors.affiliation: Mycobacteriology Laboratory Branch, Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention , Atlanta, Georgia 30333, United States.
authors.forename: Melisa J
authors.initials: MJ
authors.lastname: Willby
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Tsodikov
authors.affiliation: Mycobacteriology Laboratory Branch, Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention , Atlanta, Georgia 30333, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Posey
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
keywords: Aminoglycoside acetyltransferase; drug combination; enzyme inactivation; resistance; structure−activity relationship