Mycolic Acid Cyclopropanation is Essential for Viability, Drug Resistance, and Cell Wall Integrity of Mycobacterium tuberculosis

Daniel Barkan, Zhen Liu, James C. Sacchettini, Michael S. Glickman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Mycobacterium tuberculosis infection remains a major global health problem complicated by escalating rates of antibiotic resistance. Despite the established role of mycolic acid cyclopropane modification in pathogenesis, the feasibility of targeting this enzyme family for antibiotic development is unknown. We show through genetics and chemical biology that mycolic acid methyltransferases are essential for M. tuberculosis viability, cell wall structure, and intrinsic resistance to antibiotics. The tool compound dioctylamine, which we show acts as a substrate mimic, directly inhibits the function of multiple mycolic acid methyltransferases, resulting in loss of cyclopropanation, cell death, loss of acid fastness, and synergistic killing with isoniazid and ciprofloxacin. These results demonstrate that mycolic acid methyltransferases are a promising antibiotic target and that a family of virulence factors can be chemically inhibited with effects not anticipated from studies of each individual enzyme.

Original languageAmerican English
Pages (from-to)499-509
Number of pages11
JournalChemistry and Biology
Volume16
Issue number5
DOIs
StatePublished - 29 May 2009
Externally publishedYes

Bibliographical note

Funding Information:
The authors would like to thank Marcel Behr for kindly providing BCG Russia, Sabine Ehrt and Dirk Schnappinger for providing the tet-controlled expression system, and Susan Massarella for technical assistance. D.B. is supported in part by funds granted by the Michael and Ethel L. Cohen Foundation and by National Institutes of Health (NIH) award T32 AI055409. This work is supported by NIH award AI53417 to M.S.G. and by NIH PO1AIO68135 and the Robert A. Welch Foundation to J.C.S.

Keywords

  • CHEMBIO
  • MICROBIO

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