Methionine Aminopeptidases from Mycobacterium tuberculosis as Novel Antimycobacterial Targets

Omonike Olaleye, Tirumalai R. Raghunand, Shridhar Bhat, Jian He, Sandeep Tyagi, Gyanu Lamichhane, Peihua Gu, Jiangbing Zhou, Ying Zhang, Jacques Grosset, William R. Bishai, Jun O. Liu

Research output: Contribution to journalArticle

Abstract

Summary: Methionine aminopeptidase (MetAP) is a metalloprotease that removes the N-terminal methionine during protein synthesis. To assess the importance of the two MetAPs in Mycobacterium tuberculosis, we overexpressed and purified each of the MetAPs to near homogeneity and showed that both were active as MetAP enzymes in vitro. We screened a library of 175,000 compounds against MtMetAP1c and identified 2,3-dichloro-1,4-naphthoquinone class of compounds as inhibitors of both MtMetAPs. It was found that the MtMetAP inhibitors were active against replicating and aged nongrowing M. tuberculosis. Overexpression of either MtMetAP1a or MtMetAP1c in M. tuberculosis conferred resistance of bacterial cells to the inhibitors. Moreover, knockdown of MtMetAP1a, but not MtMetAP1c, resulted in decreased viability of M. tuberculosis. These results suggest that MtMetAP1a is a promising target for developing antituberculosis agents.

Original languageEnglish (US)
Pages (from-to)86-97
Number of pages12
JournalChemistry and Biology
Volume17
Issue number1
DOIs
StatePublished - Jan 29 2010

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Keywords

  • CHEMBIO
  • HUMDISEASE
  • MICROBIO

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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