SummaryTwo closely related pathogenic species have evolved in the genus Neisseria: N. meningitidis and N. gonorrhoeae, which occupy different host niches and cause different clinical entities. In contrast to the pathogen N. gonorrhoeae, N. meningitidis is a commensal and only rarely becomes invasive. Little is known about the genetic background of the entirely different lifestyles in these closely related species. Meningococcal NMB1843 encodes a transcriptional regulator of the MarR family. The gonococcal homologue FarR regulates expression of farAB, mediating fatty acid resistance. We show that NmFarR also directly interacts with NmfarAB. Yet, by contrast to N. gonorrhoeae, no significant sensitivity to fatty acids was observed in a DfarR mutant due to intrinsic resistance of meningococci. Further analyses identified an NmFarR-repressed protein absent from N. gonorrhoeae. This protein is the meningococcusspecific adhesin and vaccine component NadA that has most likely been acquired by horizontal gene transfer. NmFarR binds to a 16 base pair palindromic repeat within the nadA promoter. De-repression of nadA resulted in significantly higher association of a DfarR strain with epithelial cells. Hence NmFarR has gained control over a meningococcus-specific gene involved in host colonization and thus contributed to divergent niche adaptation in pathogenic Neisseriae.

Free fatty acids are important antimicrobial substances regulating the homeostasis of colonizing bacteria on epithelial surfaces. Here, we show that meningococci express a functional farAB efflux pump, which is indispensable for fatty acid resistance. However, other than in Neisseria gonorrhoeae, the transcriptional regulator FarR is not involved in regulation of this operon in Neisseria meningitidis. We tested the susceptibility of 23 meningococcal isolates against saturated and unsaturated long-chain fatty acids, proving that meningococci are generally highly resistant, with the exception of serogroup Y strains belonging to sequence type 23. Using genetically determined lipopolysaccharide (LPS)-truncated mutant strains, we show that addition of the LPS core oligosaccharide and hexa-acylation of its membrane anchor lipid A are imperative for fatty acid resistance of meningococci. The sensitivity of the serogroup Y strains is due to naturally occurring mutations within the lpxL1 gene, which is responsible for addition of the sixth acyl chain on the LPS membrane anchor lipid A. Therefore, fatty acid resistance in meningococci is provided by both the active efflux pump FarAB and by the natural permeability barrier of the Gram-negative outer membrane. The transcriptional regulator FarR is not implicated in fatty acid resistance in meningococci, possibly giving rise to a constitutively active FarAB efflux pump system and thus revealing diverse mechanisms of niche adaptation in the two closely related Neisseria species.Although humans are physiologically colonized by a vast number of microorganisms, invasion of this microflora is efficiently prevented by dermal and mucosal epithelia which form the barriers of the human body. Homeostasis of the colonizing microflora at these barriers is maintained by numerous mechanisms that include the secretion of antimicrobial compounds by the epithelia. Among these compounds are free fatty acids, which act as nonselective antimicrobials against a broad range of microorganisms. Sebaceous glands, producing a mixture of lipids called sebum, are present in the skin, the nasal epithelium, and the oral epithelium of most adults (62, 71). The produced sebum consists mainly of triglycerides which undergo hydrolysis by both host and bacterial lipases to produce free fatty acids (9). In human saliva, lipid content is about 4 to 20 mg/100 ml and includes both saturated (mainly palmitic and stearic acid) and unsaturated (mainly oleic, linoleic, palmitoleic, arachidonic, and docosahexaenoic acid) fatty acids (59, 65). Similarly, fatty acids form a major constituent of vaginal secretions (45). In most cases bacterial susceptibility to free fatty acids depends on organization of the cell wall, with Gram-negative bacteria being more resistant than Grampositive bacteria (72). Enterobacteriaceae are shielded by their lipopolysaccharide (LPS) from the antimicrobial activity of medium-and long-chain fatty acids (58). Neisseria meningitidis and Neisseria gonorrhoeae are closely related Gram-negative s...

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