A Novel Mechanism of High-Level, Broad-Spectrum Antibiotic Resistance Caused by a Single Base Pair Change in Neisseria gonorrhoeae

• Type of Material: Article
• Authors: Elizabeth A. Ohneck, Emory University; Yaramah Maxem Zalucki, Emory University; Paul J.T. Johnson, Emory University; Vijaya Dhulipala, Emory University; Daniel Golparian, Örebro University Hospital; Magnus Unemo, Örebro University Hospital; Ann E. Jerse, Uniformed Services University of the Health Sciences; William M Shafer, Emory University
• Language: English
• Date: 2011-09-20
• Publisher: American Society for Microbiology: mBio
• Publication Version: Final Published Version
• Copyright Statement: © 2011 Ohneck et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://mbio.asm.org/content/2/5/e00187-11
• Title of Journal or Parent Work: mBio
• ISSN: 2150-7511
• Volume: 2
• Issue: 5
• Start Page: e00187-11
• End Page: e00187-11
• Grant/Funding Information: W.M.S. is the recipient of a Senior Research Career Scientist Award from the VA Medical Research Service.; This work was supported by NIH grants AI021150-26; (W.M.S.) and AI031496-21 (P. F. Sparling, University of North Carolina), by a VA Merit Review Grant to W.M.S., and by grants from the Örebro County Council Research Committee and the Foundation for Medical Research at Örebro University Hospital, Örebro, Sweden (M.U.).; E.A.O. was supported in part by NIH training grant 2T32AI007470.
• Research Categories: Biology, Microbiology

Abstract

The MtrC-MtrD-MtrE multidrug efflux pump of Neisseria gonorrhoeae confers resistance to a diverse array of antimicrobial agents by transporting these toxic compounds out of the gonococcus. Frequently in gonococcal strains, the expression of the mtrCDE operon is differentially regulated by both a repressor, MtrR, and an activator, MtrA. The mtrR gene lies 250 bp upstream of and is transcribed divergently from the mtrCDE operon. Previous research has shown that mutations in the mtrR coding region and in the mtrR-mtrCDE intergenic region increase levels of gonococcal antibiotic resistance and in vivo fitness. Recently, a C-to-T transition mutation 120 bp upstream of the mtrC start codon, termed mtr120, was identified in strain MS11 and shown to be sufficient to confer high levels of antimicrobial resistance when introduced into strain FA19. Here we report that this mutation results in a consensus −10 element and that its presence generates a novel promoter for mtrCDE transcription. This newly generated promoter was found to be stronger than the wild-type promoter and does not appear to be subject to MtrR repression or MtrA activation. Although rare, the mtr120 mutation was identified in an additional clinical isolate during sequence analysis of antibiotic-resistant strains cultured from patients with gonococcal infections. We propose that cis-acting mutations can develop in gonococci that significantly alter the regulation of the mtrCDE operon and result in increased resistance to antimicrobials.