Membrane disruption by antimicrobial fatty acids releases low-molecular-weight proteins from Staphylococcus aureus

J Bacteriol. 2012 Oct;194(19):5294-304. doi: 10.1128/JB.00743-12. Epub 2012 Jul 27.

Abstract

The skin represents an important barrier for pathogens and is known to produce fatty acids that are toxic toward gram-positive bacteria. A screen of fatty acids as growth inhibitors of Staphylococcus aureus revealed structure-specific antibacterial activity. Fatty acids like oleate (18:1Δ9) were nontoxic, whereas palmitoleate (16:1Δ9) was a potent growth inhibitor. Cells treated with 16:1Δ9 exhibited rapid membrane depolarization, the disruption of all major branches of macromolecular synthesis, and the release of solutes and low-molecular-weight proteins into the medium. Other cytotoxic lipids, such as glycerol ethers, sphingosine, and acyl-amines blocked growth by the same mechanisms. Nontoxic 18:1Δ9 was used for phospholipid synthesis, whereas toxic 16:1Δ9 was not and required elongation to 18:1Δ11 prior to incorporation. However, blocking fatty acid metabolism using inhibitors to prevent acyl-acyl carrier protein formation or glycerol-phosphate acyltransferase activity did not increase the toxicity of 18:1Δ9, indicating that inefficient metabolism did not play a determinant role in fatty acid toxicity. Nontoxic 18:1Δ9 was as toxic as 16:1Δ9 in a strain lacking wall teichoic acids and led to growth arrest and enhanced release of intracellular contents. Thus, wall teichoic acids contribute to the structure-specific antimicrobial effects of unsaturated fatty acids. The ability of poorly metabolized 16:1 isomers to penetrate the cell wall defenses is a weakness that has been exploited by the innate immune system to combat S. aureus.

Publication types

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

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Cell Membrane / drug effects*
  • Cytoplasm
  • Fatty Acids / chemistry
  • Fatty Acids / pharmacology*
  • Gene Expression Regulation, Bacterial / drug effects
  • Microbial Sensitivity Tests
  • Permeability
  • Staphylococcus aureus / cytology*
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Fatty Acids

Associated data

  • GEO/GSE36231