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

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1639-1646
Number of pages8
JournalACS Chemical Biology
Volume11
Issue number6
DOIs
StatePublished - Jun 17 2016

Bibliographical note

Funding Information:
We thank S. Vander Roest, M. Larsen, and P. Kirchhoff from the CCG at the University of Michigan for help with HTS. We thank the staff of sector 22 (SER-CAT) of the Advanced Photon Source at the Argonne National Laboratories for their assistance with the remote X-ray diffraction data collection. The beamline use was supported, in part, by the Center for Structural Biology at the University of Kentucky.

Publisher Copyright:
© 2016 American Chemical Society.

Fingerprint

Dive into the research topics of 'Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis'. Together they form a unique fingerprint.

Cite this