Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis

Willby, Melisa J.; Green, Keith D.; Gajadeera, Chathurada S.; Hou, Caixia; Tsodikov, Oleg V.; Posey, James E.; Garneau-Tsodikova, Sylvie

doi:10.1021/acschembio.6b00110

Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis

Journal Article · Thu Mar 24 00:00:00 EDT 2016 · ACS Chemical Biology

DOI:https://doi.org/10.1021/acschembio.6b00110· OSTI ID:1267465

Willby, Melisa J. ^[1]; Green, Keith D. ^[2]; Gajadeera, Chathurada S. ^[2]; Hou, Caixia ^[2]; Tsodikov, Oleg V. ^[2]; Posey, James E. ^[1]; Garneau-Tsodikova, Sylvie ^[2]

Centers for Disease Control and Prevention, Atlanta, GA (United States)
Univ. of Kentucky, Lexington, KY (United States)

A major cause of tuberculosis (TB) resistance to the aminoglycoside kanamycin (KAN) is the Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. Upregulation of this enzyme is responsible for inactivation of KAN through acetylation of its amino groups. A 123 000-compound high-throughput screen (HTS) yielded several small-molecule Eis inhibitors that share an isothiazole S,S-dioxide heterocyclic core. These were investigated for their structure–activity relationships. Crystal structures of Eis in complex with two potent inhibitors show that these molecules are bound in the conformationally adaptable aminoglycoside binding site of the enzyme, thereby obstructing binding of KAN for acetylation. Importantly, we demonstrate that several Eis inhibitors, when used in combination with KAN against resistant Mtb, efficiently overcome KAN resistance. Furthermore, this approach paves the way toward development of novel combination therapies against aminoglycoside-resistant TB.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Center for Chemical Genomics (CCG); Firland Foundation; National Inst. of Health (NIH)

OSTI ID:: 1267465

Journal Information:: ACS Chemical Biology, Journal Name: ACS Chemical Biology Journal Issue: 6 Vol. 11; ISSN 1554-8929

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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