title: Sulfonamide-Based Inhibitors of Aminoglycoside Acetyltransferase Eis Abolish Resistance to Kanamycin in Mycobacterium tuberculosis.
abstract: A two-drug combination therapy where one drug targets an offending cell and the other targets a resistance mechanism to the first drug is a time-tested, yet underexploited approach to combat or prevent drug resistance. By high-throughput screening, we identified a sulfonamide scaffold that served as a pharmacophore to generate inhibitors of Mycobacterium tuberculosis acetyltransferase Eis, whose upregulation causes resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN) in Mycobacterium tuberculosis. Rational systematic derivatization of this scaffold to maximize Eis inhibition and abolish the Eis-mediated KAN resistance of M. tuberculosis yielded several highly potent agents. A crystal structure of Eis in complex with one of the most potent inhibitors revealed that the inhibitor bound Eis in the AG-binding pocket held by a conformationally malleable region of Eis (residues 28-37) bearing key hydrophobic residues. These Eis inhibitors are promising leads for preclinical development of innovative AG combination therapies against resistant TB.
authors.affiliation: University of Kentucky , Department of Pharmaceutical Sciences, College of Pharmacy, 789 South Limestone St., Lexington, Kentucky 40536-0596, 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: University of Kentucky , Department of Pharmaceutical Sciences, College of Pharmacy, 789 South Limestone St., Lexington, Kentucky 40536-0596, United States.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.affiliation: University of Kentucky , Department of Pharmaceutical Sciences, College of Pharmacy, 789 South Limestone St., Lexington, Kentucky 40536-0596, United States.
authors.forename: Chathurada S
authors.initials: CS
authors.lastname: Gajadeera
authors.affiliation: University of Kentucky , Department of Pharmaceutical Sciences, College of Pharmacy, 789 South Limestone St., Lexington, Kentucky 40536-0596, United States.
authors.forename: Caixia
authors.initials: C
authors.lastname: Hou
authors.affiliation: University of Kentucky , Department of Pharmaceutical Sciences, College of Pharmacy, 789 South Limestone St., Lexington, Kentucky 40536-0596, 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: University of Kentucky , Department of Pharmaceutical Sciences, College of Pharmacy, 789 South Limestone St., Lexington, Kentucky 40536-0596, United States.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007612:Kanamycin / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D007612:Kanamycin; D000123:Acetyltransferases; C019681:aminoglycoside acetyltransferase