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. 2016 Sep 15;7(12):1219-1221.
doi: 10.1021/acsmedchemlett.6b00261. eCollection 2016 Dec 8.

Discovery and Optimization of Two Eis Inhibitor Families as Kanamycin Adjuvants against Drug-Resistant M. tuberculosis

Atefeh Garzan  1 , Melisa J Willby  2 , Keith D Green  1 , Oleg V Tsodikov  1 , James E Posey  2 , Sylvie Garneau-Tsodikova  1
Affiliations

Discovery and Optimization of Two Eis Inhibitor Families as Kanamycin Adjuvants against Drug-Resistant M. tuberculosis

Atefeh Garzan et al. ACS Med Chem Lett. .

Abstract

Drug-resistant tuberculosis (TB) is a global threat and innovative approaches such as using adjuvants of anti-TB therapeutics are required to combat it. High-throughput screening yielded two lead scaffolds of inhibitors of Mycobacterium tuberculosis (Mtb) acetyltransferase Eis, whose upregulation causes resistance to the anti-TB drug kanamycin (KAN). Chemical optimization on these scaffolds resulted in potent Eis inhibitors. One compound restored the activity of KAN in a KAN-resistant Mtb strain. Model structures of Eis-inhibitor complexes explain the structure-activity relationship.

Keywords: Aminoglycoside acetyltransferase; drug combination; enzyme inactivation; resistance; structure−activity relationship.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Preparation of Potential Eis Inhibitors: Scaffold 1 and Scaffold 2 Core Structures Generated in This Study
See this image and copyright information in PMC

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