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

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 antimicrobi...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	antibiotic resistance efflux gonorrhea molecular genetics transformation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0768313d52f94a4392f3650a97098160
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spelling	oai:doaj.org-article:0768313d52f94a4392f3650a970981602021-11-15T15:52:19ZMechanistic 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 Locus10.1128/mBio.02281-182150-7511https://doaj.org/article/0768313d52f94a4392f3650a970981602018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02281-18https://doaj.org/toc/2150-7511ABSTRACT 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.Corinne E. Rouquette-LoughlinJennifer L. ReimcheJacqueline T. BalthazarVijaya DhulipalaKim M. GernertEllen N. KershCau D. PhamKevin PettusA. Jeanine AbramsDavid L. TreesSancta St CyrWilliam M. ShaferAmerican Society for Microbiologyarticleantibiotic resistanceeffluxgonorrheamolecular geneticstransformationMicrobiologyQR1-502ENmBio, Vol 9, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	antibiotic resistance efflux gonorrhea molecular genetics transformation Microbiology QR1-502
spellingShingle	antibiotic resistance efflux gonorrhea molecular genetics transformation Microbiology QR1-502 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 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
description	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.
format	article
author	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
author_facet	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
author_sort	Corinne E. Rouquette-Loughlin
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/0768313d52f94a4392f3650a97098160
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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

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