title: Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis.
abstract: A major cause of tuberculosis (TB) resistance to the aminoglycoside kanamycin (KAN) is the Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. Upregulation of this enzyme is responsible for inactivation of KAN through acetylation of its amino groups. A 123 000-compound high-throughput screen (HTS) yielded several small-molecule Eis inhibitors that share an isothiazole S,S-dioxide heterocyclic core. These were investigated for their structure-activity relationships. Crystal structures of Eis in complex with two potent inhibitors show that these molecules are bound in the conformationally adaptable aminoglycoside binding site of the enzyme, thereby obstructing binding of KAN for acetylation. Importantly, we demonstrate that several Eis inhibitors, when used in combination with KAN against resistant Mtb, efficiently overcome KAN resistance. This approach paves the way toward development of novel combination therapies against aminoglycoside-resistant TB.
authors.affiliation: Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention , Atlanta, Georgia 30329, United States.
authors.forename: Melisa J
authors.initials: MJ
authors.lastname: Willby
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40536-0596, United States.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40536-0596, United States.
authors.forename: Chathurada S
authors.initials: CS
authors.lastname: Gajadeera
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40536-0596, United States.
authors.forename: Caixia
authors.initials: C
authors.lastname: Hou
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40536-0596, United States.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Tsodikov
authors.affiliation: Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention , Atlanta, Georgia 30329, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Posey
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40536-0596, United States.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D057166:High-Throughput Screening Assays; D007612:Kanamycin / Q000378:metabolism / Q000494:pharmacology; D007613:Kanamycin Resistance / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D003499:Cyclic S-Oxides; D013844:Thiazoles; D007612:Kanamycin; D000123:Acetyltransferases; C430563:Eis protein, Mycobacterium tuberculosis