There is growing evidence that the role of lipids in innate immunity is more important than previously realized. How lipids interact with bacteria to achieve a level of protection, however, is still poorly understood. To begin to address the mechanisms of antibacterial activity, we determined MICs and minimum bactericidal concentrations (MBCs) of lipids common to the skin and oral cavity-the sphingoid bases D-sphingosine, phytosphingosine, and dihydrosphingosine and the fatty acids sapienic acid and lauric acid-against four Gram-negative bacteria and seven Gram-positive bacteria. Exact Kruskal-Wallis tests of these values showed differences among lipid treatments (P < 0.0001) for each bacterial species except Serratia marcescens and Pseudomonas aeruginosa. D-Sphingosine (MBC range, 0.3 to 19.6 g/ml), dihydrosphingosine (MBC range, 0.6 to 39.1 g/ml), and phytosphingosine (MBC range, 3.3 to 62.5 g/ml) were active against all bacteria except S. marcescens and P. aeruginosa (MBC > 500 g/ml). Sapienic acid (MBC range, 31.3 to 375.0 g/ml) was active against Streptococcus sanguinis, Streptococcus mitis, and Fusobacterium nucleatum but not active against Escherichia coli, Staphylococcus aureus, S. marcescens, P. aeruginosa, Corynebacterium bovis, Corynebacterium striatum, and Corynebacterium jeikeium (MBC > 500 g/ml). Lauric acid (MBC range, 6.8 to 375.0 g/ml) was active against all bacteria except E. coli, S. marcescens, and P. aeruginosa (MBC > 500 g/ml). Complete killing was achieved as early as 0.5 h for some lipids but took as long as 24 h for others. Hence, sphingoid bases and fatty acids have different antibacterial activities and may have potential for prophylactic or therapeutic intervention in infection.C ommon sphingolipids and fatty acids are involved in the physical barrier, permeability barrier, and immunologic barrier functions of the skin and oral mucosa (8,14). Epithelial layers contain ceramides, free fatty acids, and cholesterol; sebaceous lipids at the skin surface include a complex mixture of triglycerides, fatty acids, wax esters, squalene, cholesterol, and cholesterol esters; and saliva contains the same sebaceous lipids (6,14,19). These sebaceous secretions contribute to (i) the transport of fatsoluble antioxidants to the skin and mucosal surfaces, (ii) the proand anti-inflammatory properties of the skin and mucosal surfaces, and (iii) the innate antimicrobial activity of the skin and mucosal surfaces (20,26,27).Although the composition, biosynthesis, secretion, and function of cutaneous lipids are well characterized from extensive and elegant work done in the 1970s, little is known about their role in controlling microbial infection and colonization. Certain fatty acids and sphingoid bases found at the skin and mucosal surfaces are known to have antibacterial activity and are thought to play a more direct role than previously thought in innate immune defense against epidermal and mucosal bacterial infections (10). They include free sphingosines, dihydrosphingosines, lauric acid, and sapienic aci...