Regulation of the MtrC-MtrD-MtrE efflux-pump system modulates the in vivo fitness of Neisseria gonorrhoeae.
The Neisseria gonorrhoeae MtrC-MtrD-MtrE multidrug-resistance efflux pump expels macrolide antibiotics, penicillin, and antimicrobial effectors of the innate defense. Mutation of the mtrR locus, which encodes a transcriptional repressor of the mtrCDE operon, increases gonococcal resistance to these agents. Here we report that, in a mouse infection model, an mtrR mutant is more fit than the wild-type bacteria. Consistent with derepression of the mtrCDE operon as the primary reason for the fitness benefit, an mtrR,mtrE double mutant and an mtrE mutant showed no difference in survival phenotype. Gonococcal mutants deficient in MtrA, an activator of the mtrCDE operon, exhibited significantly reduced fitness in vivo, and mtrA mutants with spontaneous compensatory mtrR mutations were selected during infection. These results confirm the importance of the MtrC-MtrD-MtrE efflux-pump system during experimental gonococcal genital-tract infection and also illustrate an antibiotic-resistance mechanism that is accompanied by a fitness benefit rather than a fitness cost.
Warner
Douglas M
DM
Department of Microbiology and Immunology, F. Edward Hèbert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20853, USA.
Folster
Jason P
JP
Shafer
William M
WM
Jerse
Ann E
AE
D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics*; D006069:Gonorrhea / Q000382:microbiology; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009344:Neisseria gonorrhoeae / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D009876:Operon / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D008074:Lipoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C094589:MtrC protein, Neisseria gonorrhoeae; C107795:MtrD protein, Neisseria gonorrhoeae; C107796:MtrE protein, Neisseria gonorrhoeae; D012097:Repressor Proteins; C087450:mtrR protein, Neisseria gonorrhoeae