RESISTANCE OF NEISSERIA-GONORRHOEAE TO ANTIMICROBIAL HYDROPHOBIC AGENTS IS MODULATED BY THE MTRRCDE EFFLUX SYSTEM

The mtr (multiple transferable resistance) system of Neisseria gonorrh oeae determines levels of gonococcal resistance to hydrophobic agents (HAs), including detergent-like fatty acids and bile salts that bathe certain mucosal surfaces. The genetic organization of the mtr system w as determined and found to consist of the mtrR gene, which encodes a t ranscriptional regulator (MtrR), and three tandemly linked genes terme d mtrCDE. The mtrCDE genes were organized in the same apparent transcr iptional unit, upstream and divergent from the mtrR gene. The mtrCDE-e ncoded proteins of N. gonorrhoeae were analogous to a family of bacter ial efflux/transport proteins, notable the MexABOprK proteins of Pseud omonas aeruginosa and the AcrAE and EnvCD proteins of Escherichia coli , that mediate resistance to drugs, dyes, and detergents. Inactivation of the mtrC gene resulted in loss of the MtrC lipoprotein and rendere d gonococci hypersusceptible to structurally diverse HAs; this reveale d the importance of the mtr system in determining HA(R) in gonococci. Further support for a role of the mtrCDE gene complex in determining l evels of HA(R) in gonococci was evident when transformants bearing mut ations in the mtrR gene were analysed. In this respect, missense and a nd null mutations in the mtrR gene were found to result in increased l evels of MtrC and HA(R). However, high levels of MtrC and HA(R), simil ar to those observed for clinical isolates, were associated with a sin gle bp deletion in a 13 bp inverted repeat sequence that intervened th at divergent mtrR and mtrC genes. We propose that the 13 bp inverted-r epeat sequence represents a transcriptional control element that regul ates expression of the mtrRCDE gene complex, thereby modulating levels of gonococcal susceptibility to HAs.