Potent 1,2,4-Triazino[5,6 b ]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis

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

doi:10.1021/acsinfecdis.8b00074

Title: Potent 1,2,4-Triazino[5,6 b ]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis

Journal Article · Fri Mar 30 00:00:00 EDT 2018 · ACS Infectious Diseases

DOI:https://doi.org/10.1021/acsinfecdis.8b00074· OSTI ID:1464833

Ngo, Huy X. ^[1]; Green, Keith D. ^[1]; Gajadeera, Chathurada S. ^[1]; Willby, Melisa J. ^[2]; Holbrook, Selina Y. L. ^[1]; Hou, Caixia ^[1]; Garzan, Atefeh ^[1];

^[3]; Posey, James E. ^[2];

^[1];

^[4]

Univ. of Kentucky, Lexington, KY (United States)
Centers for Disease Control and Prevention, Atlanta, GA (United States). National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Division of Tuberculosis Elimination
Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of Kentucky, Lexington, KY (United States); Univ. of Michigan, Ann Arbor, MI (United States)

A common cause of resistance to kanamycin (KAN) in tuberculosis is overexpression of the enhanced intracellular survival (Eis) protein. Eis is an acetyltransferase that multiacetylates KAN and other aminoglycosides, rendering them unable to bind the bacterial ribosome. By high-throughput screening, a series of substituted 1,2,4-triazino[5,6b]indole-3-thioether molecules were identified as effective Eis inhibitors. In this work, we purchased 17 and synthesized 22 new compounds, evaluated their potency, and characterized their steady-state kinetics. Four inhibitors were found not only to inhibit Eis in vitro, but also to act as adjuvants of KAN and partially restore KAN sensitivity in a Mycobacterium tuberculosis KAN-resistant strain in which Eis is upregulated. A crystal structure of Eis in complex with a potent inhibitor and CoA shows that the inhibitors bind in the aminoglycoside binding site snugly inserted into a hydrophobic cavity. These inhibitors will undergo preclinical development as novel KAN adjuvant therapies to treat KAN-resistant tuberculosis.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); Firland Foundation; Center for Chemical Genomics (CCG); University of Kentucky

Grant/Contract Number:: AI090048

OSTI ID:: 1464833

Journal Information:: ACS Infectious Diseases, Vol. 4, Issue 6; ISSN 2373-8227

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 17 works

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Mycobacterial Aminoglycoside Acetyltransferases: A Little of Drug Resistance, and a Lot of Other Roles Sanz-García, Fernando; Anoz-Carbonell, Ernesto; Pérez-Herrán, Esther Frontiers in Microbiology, Vol. 10 https://doi.org/10.3389/fmicb.2019.00046	journal	January 2019
The Role of Antibiotic-Target-Modifying and Antibiotic-Modifying Enzymes in Mycobacterium abscessus Drug Resistance Luthra, Sakshi; Rominski, Anna; Sander, Peter Frontiers in Microbiology, Vol. 9 https://doi.org/10.3389/fmicb.2018.02179	journal	September 2018

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