Mechanistic Basis for Decreased Antimicrobial Susceptibility in a Clinical Isolate of Neisseria gonorrhoeae Possessing a Mosaic-Like mtr Efflux Pump Locus

• Type of Material: Article
• Authors: Corinne Loughlin, Emory University; Jennifer L. Reimche, Emory University; Jacqueline T. Balthazar, Emory University; Vijaya Dhulipala, Emory University; Kim M. Gernert, Centers for Disease Control and Prevention; Ellen N. Kersh, Centers for Disease Control and Prevention; Cau D. Pham, Centers for Disease Control and Prevention; Kevin Pettus, Centers for Disease Control and Prevention; A. Jeanine Abrams, Centers for Disease Control and Prevention; David L. Trees, Centers for Disease Control and Prevention; Sancta St Cyr, Centers for Disease Control and Prevention; William M Shafer, Emory University
• Language: English
• Date: 2018-11-01
• Publisher: American Society for Microbiology: Open Access Journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018, American Society for Microbiology. All rights reserved.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/mBio.02281-18
• Title of Journal or Parent Work: mBio
• ISSN: 2150-7511
• Volume: 9
• Issue: 6
• Grant/Funding Information: CDC-based coauthors were funded by CDC. Their work was in part made possible through support from CDC’s Advanced Molecular Detection (AMD-18) and Combating Antibiotic Resistant Bacteria (CARB) programs.; The contents of this article are solely the responsibility of the authors and do not necessarily reflect the official views of the National Institutes of Health, the Centers for Disease Control and Prevention, the U.S. Department of Veterans Affairs, or the United States government.; W.M.S. is the recipient of a Senior Research Career Scientist Award from the Biomedical Laboratory Research and Development Service of the U.S. Department of Veterans Affairs.; This work was supported by NIH grant R37AI21150-33 (W.M.S.) and funds from an Intergovernmental Personnel Act from the CDC to C.E.R.-L., J.L.R., and W.M.S.
• Keywords: Science & Technology; SPECTRUM CEPHALOSPORINS; HIGH-LEVEL; Microbiology; SURVEILLANCE; transformation; 1ST STRAIN; GENES; antibiotic resistance; efflux; AZITHROMYCIN; PENICILLIN RESISTANCE; Life Sciences & Biomedicine; gonorrhea; MUTATIONS; GENOMIC EPIDEMIOLOGY; molecular genetics; SYSTEM
• Research Categories: Biology, Microbiology; Biology, Genetics

Abstract

Recent reports suggest that mosaic-like sequences within the mtr (mul-tiple transferable resistance) efflux pump locus of Neisseria gonorrhoeae, likely originating from commensal Neisseria sp. by transformation, can increase the ability of gonococci to resist structurally diverse antimicrobials. Thus, acquisition of numerous nucleotide changes within the mtrR gene encoding the transcriptional repressor (MtrR) of the mtrCDE efflux pump-encoding operon or overlapping promoter region for both along with those that cause amino acid changes in the MtrD transporter protein were recently reported to decrease gonococcal susceptibility to numerous antimicrobials, including azithromycin (Azi) (C. B. Wadsworth, B. J. Arnold, M. R. A. Satar, and Y. H. Grad, mBio 9:e01419-18, 2018, https://doi.org/10.1128/mBio.01419-18). We performed detailed genetic and molecular studies to define the mechanistic basis for why such strains can exhibit decreased susceptibility to MtrCDE antimicrobial substrates, including Azi. We report that a strong cis-acting transcriptional impact of a single nucleotide change within the –35 hexamer of the mtrCDE promoter as well gain-of-function amino acid changes at the C-terminal region of MtrD can mechanis-tically account for the decreased antimicrobial susceptibility of gonococci with a mosaic-like mtr locus. IMPORTANCE Historically, after introduction of an antibiotic for treatment of gonorrhea, strains of N. gonorrhoeae emerge that display clinical resistance due to spontaneous mutation or acquisition of resistance genes. Genetic exchange between members of the Neisseria genus occurring by transformation can cause significant changes in gonococci that impact the structure of an antibiotic target or expression of genes involved in resistance. The results presented here provide a framework for understanding how mosaic-like DNA sequences from commensal Neisseria that recombine within the gonococcal mtr efflux pump locus function to decrease bacterial susceptibility to antimicrobials, including antibiotics used in therapy of gonorrhea.