Transcriptional Control of themtrEfflux System ofNeisseria gonorrhoeae

The capacity ofNeisseria gonorrhoeaeto resist structurally diverse hydrophobic agents (HAs) because of the mtr(multiple transferrable resistance) efflux system was found to be regulated at the level of transcription by two distinct mechanisms. This was surmised because a deletion that removed >90% of the coding sequence of the mtrR (multiple transferrable resistance regulator) gene or a single-base-pair deletion within a 13-bp inverted repeat sequence located in its promoter resulted in altered expression of themtrCgene;mtrCencodes a 44-kDa membrane lipoprotein essential for the efflux of HAs. However, the single-base-pair deletion had the more significant impact on gene expression since it resulted in the loss of expression ofmtrRand a threefold increaseintheexpressionofmtrC.Hence,themtreffluxsystemingonococciissubjecttobothMtrR-dependent and MtrR-independent regulation, and the levels of mtrC mRNA correlate well with HA resistance levels in gonococci. Thegeneticorganizationofthemtrsystemingonococci(17) was recently determined (4, 12) and was found to be remark- ably similar to that of themexAB-oprKefflux system ofPseudo- monas aeruginosa (13) as well as those of the acrAE (7) and envCD (5) efflux pumps possessed by Escherichia coli; the E. coli efflux operons have been renamed acrAB and acrEF, re- spectively (8). Recent studies confirmed (6) the energy-depen- dent efflux action capacity of the mtr system. As was empha- sized in a recent review by Nikaido (11), efflux systems have importance for bacterial resistance to structurally diverse an- timicrobial agents, including antibiotics, dyes, and detergents. Efflux systems may be of importance for gonococcal survival in hostile environments rich in hydrophobic agents (HAs) since clinical isolates expressing resistance to multiple HAs because ofmtrare frequently recovered from patients (10), particularly those with rectal infections in which toxic fecal lipids and bile salts are likely to select for resistant variants in vivo (9). The mtrR-encoded protein resembles numerous transcrip- tional repressors (12), such as the tetracycline repressor of pSC101(2),andatleastoneactivatoroftranscription,LuxRof Vibrio harveyi (18). The mtrCDE gene complex probably con- stitutes a single transcriptional unit since promoter sequences have not been found between these genes (4). The mtrCDE operon is positioned 250 bp upstream of and is divergently transcribed from the mtrR gene. Mutations within the mtrR coding or promoter region were found (4) to result in both enhanced levels of HA resistance and elevated levels of MtrC, a 44-kDa lipoprotein that resembles members of the mem- brane fusion protein family (14) essential for the efflux of antimicrobial agents (11). Missense mutations in mtrR that resultinradicalaminoacidreplacementswithinthehelix-turn-