Dual inhibition of mycobacterial fatty acid biosynthesis and degradation by 2-alkynoic acids

Chem Biol. 2006 Mar;13(3):297-307. doi: 10.1016/j.chembiol.2006.01.005.

Abstract

2-Hexadecynoic acid and 2-octadecynoic acid have cidal activity against Mycobacterium smegmatis and Mycobacterium bovis BCG. At subinhibitory concentrations, M. smegmatis rapidly transformed [1-(14)C]-2-hexadecynoic acid into endogenous fatty acids and elongated them into mycolic acids. Toxic concentrations of 2-hexadecynoic acid resulted in accumulation of 3-ketohexadecanoic acid, which blocked fatty acid biosynthesis, and 3-hexadecynoic acid, an inhibitor of fatty acid degradation. The combination of these two metabolites is necessary to achieve the inhibition of M. smegmatis. We conclude that 2- and 3-hexa/octadecynoic acids inhibit mycolic acid biosynthesis, fatty acid biosynthesis, and fatty acid degradation, pathways of significant importance for mycobacteria.

Publication types

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

MeSH terms

  • Alkynes / pharmacology
  • Anti-Bacterial Agents / pharmacology*
  • Fatty Acids / biosynthesis
  • Fatty Acids / metabolism*
  • Fatty Acids, Unsaturated / pharmacology*
  • Models, Chemical
  • Mycobacterium / drug effects*
  • Mycobacterium / metabolism
  • Mycobacterium bovis / drug effects
  • Mycobacterium bovis / metabolism
  • Mycobacterium smegmatis / drug effects
  • Mycobacterium smegmatis / metabolism
  • Mycolic Acids / antagonists & inhibitors
  • Mycolic Acids / metabolism

Substances

  • 2-octadecynoic acid
  • Alkynes
  • Anti-Bacterial Agents
  • Fatty Acids
  • Fatty Acids, Unsaturated
  • Mycolic Acids
  • 2-hexadecynoic acid