Discovery and Mechanistic Analysis of Structurally Diverse Inhibitors of Acetyltransferase Eis among FDA-Approved Drugs

Allan H. Pang, Keith D. Green, Ankita Punetha, Nishad Thamban Chandrika, Kaitlind C. Howard, Sylvie Garneau-Tsodikova, Oleg V. Tsodikov

Research output: Contribution to journalArticlepeer-review

Abstract

Over one and a half million people die of tuberculosis (TB) each year. Multidrug-resistant TB infections are especially dangerous, and new drugs are needed to combat them. The high cost and complexity of drug development make repositioning of drugs that are already in clinical use for other indications a potentially time- and money-saving avenue. In this study, we identified among existing drugs five compounds: azelastine, venlafaxine, chloroquine, mefloquine, and proguanil as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis, a causative agent of TB. Eis upregulation is a cause of clinically relevant resistance of TB to kanamycin, which is inactivated by Eis-catalyzed acetylation. Crystal structures of these drugs as well as chlorhexidine in complexes with Eis showed that these inhibitors were bound in the aminoglycoside binding cavity, consistent with their established modes of inhibition with respect to kanamycin. Among three additionally synthesized compounds, a proguanil analogue, designed based on the crystal structure of the Eis-proguanil complex, was 3-fold more potent than proguanil. The crystal structures of these compounds in complexes with Eis explained their inhibitory potencies. These initial efforts in rational drug repositioning can serve as a starting point in further development of Eis inhibitors.

Original languageEnglish
Pages (from-to)710-721
Number of pages12
JournalBiochemistry
Volume62
Issue number3
DOIs
StatePublished - Feb 7 2023

Bibliographical note

Funding Information:
This study was funded by grants from the National Institutes of Health (NIH) AI090048 (to S.G.-T.), the Firland Foundation (to S.G.-T.), and the Center for Chemical Genomics (CCG) at the University of Michigan (to S.G.-T.), as well as by startup funds from the College of Pharmacy at the University of Kentucky (to S.G.-T. and O.V.T). The authors acknowledge S. Vander Roest, M. Larsen, and P. Kirchhoff from the CCG at the University of Michigan for their help with HTS. They also extend their appreciation to Abdelrahman S. Mayhoub for helping with the selection of FDA-approved drugs for screening. They thank the staff of sector SER-CAT of the Advanced Photon Source at the Argonne National Laboratories for assistance with remote X-ray diffraction data collection. The synchrotron access was supported, in part, by the Center for Structural Biology at the University of Kentucky. The authors thank the College of Pharmacy NMR Center (University of Kentucky) for NMR support. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agencies.

Publisher Copyright:
© 2023 American Chemical Society.

ASJC Scopus subject areas

  • Biochemistry

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