Bactericidal Activity of the Human Skin Fatty Acid cis-6-Hexadecanoic Acid on Staphylococcus aureus

Human skin fatty acids are a potent aspect of our innate defenses, giving surface protection against potentially invasive organ-isms. They provide an important parameter in determining the ecology of the skin microflora, and alterations can lead to in-creased colonization by pathogens such as Staphylococcus aureus. Harnessing skin fatty acids may also give a new avenue of ex-ploration in the generation of control measures against drug-resistant organisms. Despite their importance, the mechanism(s) whereby skin fatty acids kill bacteria has remained largely elusive. Here, we describe an analysis of the bactericidal effects of the major human skin fatty acid cis-6-hexadecenoic acid (C6H) on the human commensal and pathogen S. aureus. Several C6H con-centration-dependent mechanisms were found. At high concentrations, C6H swiftly kills cells associated with a general loss of membrane integrity. However, C6H still kills at lower concentrations, acting through disruption of the protonmotive force, an increase in membrane fluidity, and its effects on electron transfer. The design of analogues with altered bactericidal effects has begun to determine the structural constraints on activity and paves the way for the rational design of new antistaphylococcal agents. The human skin provides important protection against micro-bial infection. The epidermis provides a physical barrier via an external cross-linked keratin layer upon a scaffold of keratino-cytes. Most importantly, the skin also has a broad range of innate immunity components, including antimicrobial peptides an