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

Atefeh Garzan; Melisa J. Willby; Keith D. Green; Oleg V. Tsodikov; James E. Posey; Sylvie Garneau-Tsodikova

doi:10.1021/acsmedchemlett.6b00261

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

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

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English
Pages (from-to)	1219-1221
Number of pages	3
Journal	ACS Medicinal Chemistry Letters
Volume	7
Issue number	12
DOIs	https://doi.org/10.1021/acsmedchemlett.6b00261
State	Published - Dec 8 2016

Bibliographical note

Funding Information:
This work was supported by a NIH Grant AI090048 (S.G.-T.), a grant from theCCGat the U. Michigan (S.G.-T.), a grant from the Firland Foundation (S.G.-T.), and by startup funds from the College of Pharmacy at the U. Kentucky (S.G.-T. and O.V.T.).We thank Steve Vander Roest, Martha Larsen, and Paul Kirchhoff (CCG, UM) for help with HTS.

Publisher Copyright:
© 2016 American Chemical Society.

Keywords

Aminoglycoside acetyltransferase
drug combination
enzyme inactivation
resistance
structure−activity relationship

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acsmedchemlett.6b00261

Cite this

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

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.",

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note = "Funding Information: This work was supported by a NIH Grant AI090048 (S.G.-T.), a grant from theCCGat the U. Michigan (S.G.-T.), a grant from the Firland Foundation (S.G.-T.), and by startup funds from the College of Pharmacy at the U. Kentucky (S.G.-T. and O.V.T.).We thank Steve Vander Roest, Martha Larsen, and Paul Kirchhoff (CCG, UM) for help with HTS. Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

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doi = "10.1021/acsmedchemlett.6b00261",

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AU - Garzan, Atefeh

AU - Willby, Melisa J.

AU - Green, Keith D.

AU - Tsodikov, Oleg V.

AU - Posey, James E.

AU - Garneau-Tsodikova, Sylvie

N1 - Funding Information: This work was supported by a NIH Grant AI090048 (S.G.-T.), a grant from theCCGat the U. Michigan (S.G.-T.), a grant from the Firland Foundation (S.G.-T.), and by startup funds from the College of Pharmacy at the U. Kentucky (S.G.-T. and O.V.T.).We thank Steve Vander Roest, Martha Larsen, and Paul Kirchhoff (CCG, UM) for help with HTS. Publisher Copyright: © 2016 American Chemical Society.

PY - 2016/12/8

Y1 - 2016/12/8

N2 - 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.

AB - 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.

KW - Aminoglycoside acetyltransferase

KW - drug combination

KW - enzyme inactivation

KW - resistance

KW - structure−activity relationship

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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