Discovery of substituted benzyloxy-benzylamine inhibitors of acetyltransferase Eis and their anti-mycobacterial activity

Allan H. Pang, Keith D. Green, Nishad Thamban Chandrika, Atefeh Garzan, Ankita Punetha, Selina Y.L. Holbrook, Melisa J. Willby, James E. Posey, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

A clinically significant mechanism of tuberculosis resistance to the aminoglycoside kanamycin (KAN) is its acetylation catalyzed by upregulated Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. In search for inhibitors of Eis, we discovered an inhibitor with a substituted benzyloxy-benzylamine scaffold. A structure-activity relationship study of 38 compounds in this structural family yielded highly potent (IC50 ∼ 1 μM) Eis inhibitors, which did not inhibit other acetyltransferases. Crystal structures of Eis in complexes with three of the inhibitors showed that the inhibitors were bound in the aminoglycoside binding site of Eis, consistent with the competitive mode of inhibition, as established by kinetics measurements. When tested in Mtb cultures, two inhibitors (47 and 55) completely abolished resistance to KAN of the highly KAN-resistant strain Mtb mc2 6230 K204, likely due to Eis inhibition as a major mechanism. Thirteen of the compounds were toxic even in the absence of KAN to Mtb and other mycobacteria, but not to non-mycobacteria or to mammalian cells. This, yet unidentified mechanism of toxicity, distinct from Eis inhibition, will merit future studies along with further development of these molecules as anti-mycobacterial agents.

Original languageEnglish
Article number114698
JournalEuropean Journal of Medicinal Chemistry
Volume242
DOIs
StatePublished - Nov 15 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Masson SAS

Keywords

  • Crystal structure
  • Drug resistance
  • Enhanced intracellular survival
  • Enzyme kinetics
  • Mycobacterium tuberculosis
  • Structure-activity relationship
  • Tuberculosis

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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