Mechanistic Basis for Decreased Antimicrobial Susceptibility in a Clinical Isolate of <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> Possessing a Mosaic-Like <italic toggle="yes">mtr</italic> Efflux Pump Locus
Corinne E. Rouquette-Loughlin,
Jennifer L. Reimche,
Jacqueline T. Balthazar,
Vijaya Dhulipala,
Kim M. Gernert,
Ellen N. Kersh,
Cau D. Pham,
Kevin Pettus,
A. Jeanine Abrams,
David L. Trees,
Sancta St Cyr,
William M. Shafer
Affiliations
Corinne E. Rouquette-Loughlin
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
Jennifer L. Reimche
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
Jacqueline T. Balthazar
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
Vijaya Dhulipala
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
Kim M. Gernert
Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Atlanta, Georgia, USA
Ellen N. Kersh
Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Atlanta, Georgia, USA
Cau D. Pham
Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Atlanta, Georgia, USA
Kevin Pettus
Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Atlanta, Georgia, USA
A. Jeanine Abrams
Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Atlanta, Georgia, USA
David L. Trees
Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Atlanta, Georgia, USA
Sancta St Cyr
Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Atlanta, Georgia, USA
William M. Shafer
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA
ABSTRACT Recent reports suggest that mosaic-like sequences within the mtr (multiple 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 mechanistically 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.
