Sulfonamide-Based Inhibitors of Aminoglycoside Acetyltransferase Eis Abolish Resistance to Kanamycin in Mycobacterium tuberculosis

Atefeh Garzan, 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

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10619-10628
Number of pages10
JournalJournal of medicinal chemistry
Volume59
Issue number23
DOIs
StatePublished - Dec 8 2016

Bibliographical note

Funding Information:
This work was funded by a National Institutes of Health (NIH) grant AI090048 (S.G.-T.), a grant from the Center for Chemical Genomics (CCG) at the University of Michigan (S.G.-T.), a grant from the Firland Foundation (S.G.-T.), as well as by startup funds from the College of Pharmacy at the University of Kentucky (S.G.-T. and O.V.T.). We thank Steve Vander Roest, Martha Larsen, and Paul Kirchhoff (CCG, 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.

Publisher Copyright:
© 2016 American Chemical Society

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