Mycolic acid cyclopropanation is essential for viability, drug resistance, and cell wall integrity of Mycobacterium tuberculosis

Chem Biol. 2009 May 29;16(5):499-509. doi: 10.1016/j.chembiol.2009.04.001.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemistry
  • Amines / pharmacology*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Cell Wall / chemistry
  • Cyclopropanes / chemistry*
  • Drug Resistance, Bacterial
  • Methyltransferases / antagonists & inhibitors
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Mycobacterium tuberculosis / growth & development
  • Mycolic Acids / chemistry*
  • Mycolic Acids / metabolism
  • Phenotype
  • Structure-Activity Relationship


  • Amines
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • CmaA2 protein, Mycobacterium tuberculosis
  • Cyclopropanes
  • Mycolic Acids
  • Methyltransferases
  • octylamine

Associated data

  • PDB/3HEM