Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis

Melisa J. Willby, Keith D. Green, Chathurada S. Gajadeera, Caixia Hou, Oleg V. Tsodikov, James E. Posey, Sylvie Garneau-Tsodikova

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish
Pages (from-to)1639-1646
Number of pages8
JournalACS Chemical Biology
Issue number6
StatePublished - Jun 17 2016

Bibliographical note

Publisher Copyright:
© 2016 American Chemical Society.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine


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