Combating Enhanced Intracellular Survival (Eis)-Mediated Kanamycin Resistance of Mycobacterium tuberculosis by Novel Pyrrolo[1,5-a]pyrazine-Based Eis Inhibitors

Atefeh Garzan; Melisa J. Willby; Huy X. Ngo; Chathurada S. Gajadeera; Keith D. Green; Selina Y.L. Holbrook; Caixia Hou; James E. Posey; Oleg V. Tsodikov; Sylvie Garneau-Tsodikova

doi:10.1021/acsinfecdis.6b00193

Combating Enhanced Intracellular Survival (Eis)-Mediated Kanamycin Resistance of Mycobacterium tuberculosis by Novel Pyrrolo[1,5-a]pyrazine-Based Eis Inhibitors

Atefeh Garzan, Melisa J. Willby, Huy X. Ngo, Chathurada S. Gajadeera, Keith D. Green, Selina Y.L. Holbrook, Caixia Hou, James E. Posey, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova

Food Science and Nutrition

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

42 Scopus citations

Abstract

Tuberculosis (TB) remains one of the leading causes of mortality worldwide. Hence, the identification of highly effective antitubercular drugs with novel modes of action is crucial. In this paper, we report the discovery and development of pyrrolo[1,5-a]pyrazine-based analogues as highly potent inhibitors of the Mycobacterium tuberculosis (Mtb) acetyltransferase enhanced intracellular survival (Eis), whose up-regulation causes clinically observed resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN). We performed a structure-activity relationship (SAR) study to optimize these compounds as potent Eis inhibitors both against purified enzyme and in mycobacterial cells. A crystal structure of Eis in complex with one of the most potent inhibitors reveals that the compound is bound to Eis in the AG binding pocket, serving as the structural basis for the SAR. These Eis inhibitors have no observed cytotoxicity to mammalian cells and are promising leads for the development of innovative AG adjuvant therapies against drug-resistant TB.

Original language	English (US)
Pages (from-to)	302-309
Number of pages	8
Journal	ACS Infectious Diseases
Volume	3
Issue number	4
DOIs	https://doi.org/10.1021/acsinfecdis.6b00193
State	Published - Apr 14 2017

Bibliographical note

Funding Information:
This study was funded by a National Institutes of Health (NIH) Grant AI090048 (S.G.-T.) a grant from the Firland Foundation (S.G.-T.), a grant from the Center for Chemical Genomics (CCG) at the University of Michigan (S.G.-T) and startup funds from the College of Pharmacy at the University of Kentucky (S.G.-T. and O.V.T.). S.Y.L.H. is partially supported by a University of Kentucky Presidential Fellowship.

Publisher Copyright:
© 2017 American Chemical Society.

Keywords

aminoglycoside acetyltransferase
bacterial resistance
drug combination
enzyme inactivation
structure-activity-relationship analysis

UN SDGs

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

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10.1021/acsinfecdis.6b00193

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971065

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Garzan, A., Willby, M. J., Ngo, H. X., Gajadeera, C. S., Green, K. D., Holbrook, S. Y. L., Hou, C., Posey, J. E., Tsodikov, O. V., & Garneau-Tsodikova, S. (2017). Combating Enhanced Intracellular Survival (Eis)-Mediated Kanamycin Resistance of Mycobacterium tuberculosis by Novel Pyrrolo[1,5-a]pyrazine-Based Eis Inhibitors. ACS Infectious Diseases, 3(4), 302-309. https://doi.org/10.1021/acsinfecdis.6b00193

Garzan, A, Willby, MJ, Ngo, HX, Gajadeera, CS, Green, KD, Holbrook, SYL, Hou, C, Posey, JE, Tsodikov, OV & Garneau-Tsodikova, S 2017, 'Combating Enhanced Intracellular Survival (Eis)-Mediated Kanamycin Resistance of Mycobacterium tuberculosis by Novel Pyrrolo[1,5-a]pyrazine-Based Eis Inhibitors', ACS Infectious Diseases, vol. 3, no. 4, pp. 302-309. https://doi.org/10.1021/acsinfecdis.6b00193

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abstract = "Tuberculosis (TB) remains one of the leading causes of mortality worldwide. Hence, the identification of highly effective antitubercular drugs with novel modes of action is crucial. In this paper, we report the discovery and development of pyrrolo[1,5-a]pyrazine-based analogues as highly potent inhibitors of the Mycobacterium tuberculosis (Mtb) acetyltransferase enhanced intracellular survival (Eis), whose up-regulation causes clinically observed resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN). We performed a structure-activity relationship (SAR) study to optimize these compounds as potent Eis inhibitors both against purified enzyme and in mycobacterial cells. A crystal structure of Eis in complex with one of the most potent inhibitors reveals that the compound is bound to Eis in the AG binding pocket, serving as the structural basis for the SAR. These Eis inhibitors have no observed cytotoxicity to mammalian cells and are promising leads for the development of innovative AG adjuvant therapies against drug-resistant TB.",

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AU - Ngo, Huy X.

AU - Gajadeera, Chathurada S.

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AU - Posey, James E.

AU - Tsodikov, Oleg V.

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N2 - Tuberculosis (TB) remains one of the leading causes of mortality worldwide. Hence, the identification of highly effective antitubercular drugs with novel modes of action is crucial. In this paper, we report the discovery and development of pyrrolo[1,5-a]pyrazine-based analogues as highly potent inhibitors of the Mycobacterium tuberculosis (Mtb) acetyltransferase enhanced intracellular survival (Eis), whose up-regulation causes clinically observed resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN). We performed a structure-activity relationship (SAR) study to optimize these compounds as potent Eis inhibitors both against purified enzyme and in mycobacterial cells. A crystal structure of Eis in complex with one of the most potent inhibitors reveals that the compound is bound to Eis in the AG binding pocket, serving as the structural basis for the SAR. These Eis inhibitors have no observed cytotoxicity to mammalian cells and are promising leads for the development of innovative AG adjuvant therapies against drug-resistant TB.

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Combating Enhanced Intracellular Survival (Eis)-Mediated Kanamycin Resistance of Mycobacterium tuberculosis by Novel Pyrrolo[1,5-a]pyrazine-Based Eis Inhibitors

Abstract

Bibliographical note

Keywords

UN SDGs

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