Membrane Disruption by Antimicrobial Fatty Acids Releases Low-Molecular-Weight Proteins from Staphylococcus aureus

• Published in: Journal of Bacteriology Vol. 194; no. 19; pp. 5294 - 5304
• Main Authors: Parsons, Joshua B, Yao, Jiangwei, Frank, Matthew W, Jackson, Pamela, Rock, Charles O
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.10.2012
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibacterial properties; Antimicrobial agents; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Bacteriology; Biological and medical sciences; Cell Membrane - drug effects; cell walls; Cytoplasm; Cytotoxicity; ethers; fatty acid metabolism; Fatty acids; Fatty Acids - chemistry; Fatty Acids - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Bacterial - drug effects; glycerol; Gram-positive bacteria; growth arrest; innate immunity; isomers; Membranes; Microbial Sensitivity Tests; Microbiology; Miscellaneous; oleic acid; pathogens; Permeability; phospholipids; Proteins; solutes; sphingosine; Staphylococcus aureus; Staphylococcus aureus - cytology; Staphylococcus aureus - drug effects; Staphylococcus aureus - metabolism; Staphylococcus infections; Structure-Activity Relationship; Bacteria; Lipids; Micrococcales; Micrococcaceae; Fatty acids; Antimicrobial agent; Release; Protein; Staphylococcus aureus
• ISSN: 0021-9193; 1098-5530; 1067-8832
• DOI: 10.1128/JB.00743-12

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.