Could Dampening Expression of the <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> <italic toggle="yes">mtrCDE</italic>-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?

ABSTRACT Neisseria gonorrhoeae has developed resistance to every antibiotic introduced for treatment of gonorrhea since 1938, and concern now exists that gonorrheal infections may become refractory to all available antibiotics approved for therapy. The current recommended dual antibiotic treatment r...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Shaochun Chen, Kristie L. Connolly, Corinne Rouquette-Loughlin, Alexander D’Andrea, Ann E. Jerse, William M. Shafer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Neisseria gonorrhoeae efflux pumps penicillin transcriptional regulation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9ae04b887f90467b992a0deffeba228d
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:9ae04b887f90467b992a0deffeba228d
record_format	dspace
spelling	oai:doaj.org-article:9ae04b887f90467b992a0deffeba228d2021-11-15T16:22:09ZCould Dampening Expression of the <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> <italic toggle="yes">mtrCDE</italic>-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?10.1128/mBio.01576-192150-7511https://doaj.org/article/9ae04b887f90467b992a0deffeba228d2019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01576-19https://doaj.org/toc/2150-7511ABSTRACT Neisseria gonorrhoeae has developed resistance to every antibiotic introduced for treatment of gonorrhea since 1938, and concern now exists that gonorrheal infections may become refractory to all available antibiotics approved for therapy. The current recommended dual antibiotic treatment regimen of ceftriaxone (CRO) and azithromycin (AZM) is threatened with the emergence of gonococcal strains displaying resistance to one or both of these antibiotics. Non-beta-lactamase resistance to penicillin and third-generation cephalosporins, as well as low-level AZM resistance expressed by gonococci, requires overexpression of the mtrCDE-encoded efflux pump, which in wild-type (WT) strains is subject to transcriptional repression by MtrR. Since earlier studies showed that loss of MtrCDE renders gonococci hypersusceptible to beta-lactams and macrolides, we hypothesized that transcriptional dampening of mtrCDE would render an otherwise resistant strain susceptible to these antibiotics as assessed by antibiotic susceptibility testing and during experimental infection. In order to test this hypothesis, we ectopically expressed a WT copy of the mtrR gene, which encodes the repressor of the mtrCDE efflux pump operon, in N. gonorrhoeae strain H041, the first reported gonococcal strain to cause a third-generation-cephalosporin-resistant infection. We now report that MtrR production can repress the expression of mtrCDE, increase antimicrobial susceptibility in vitro, and enhance beta-lactam efficacy in eliminating gonococci as assessed in a female mouse model of lower genital tract infection. We propose that strategies that target the MtrCDE efflux pump should be considered to counteract the increasing problem of antibiotic-resistant gonococci. IMPORTANCE The emergence of gonococcal strains resistant to past or currently used antibiotics is a global public health concern, given the estimated 78 million infections that occur annually. The dearth of new antibiotics to treat gonorrhea demands that alternative curative strategies be considered to counteract antibiotic resistance expressed by gonococci. Herein, we show that decreased expression of a drug efflux pump that participates in gonococcal resistance to antibiotics can increase gonococcal susceptibility to beta-lactams and macrolides under laboratory conditions, as well as improve antibiotic-mediated clearance of gonococci from the genital tract of experimentally infected female mice.Shaochun ChenKristie L. ConnollyCorinne Rouquette-LoughlinAlexander D’AndreaAnn E. JerseWilliam M. ShaferAmerican Society for MicrobiologyarticleNeisseria gonorrhoeaeefflux pumpspenicillintranscriptional regulationMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neisseria gonorrhoeae efflux pumps penicillin transcriptional regulation Microbiology QR1-502
spellingShingle	Neisseria gonorrhoeae efflux pumps penicillin transcriptional regulation Microbiology QR1-502 Shaochun Chen Kristie L. Connolly Corinne Rouquette-Loughlin Alexander D’Andrea Ann E. Jerse William M. Shafer Could Dampening Expression of the <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> <italic toggle="yes">mtrCDE</italic>-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?
description	ABSTRACT Neisseria gonorrhoeae has developed resistance to every antibiotic introduced for treatment of gonorrhea since 1938, and concern now exists that gonorrheal infections may become refractory to all available antibiotics approved for therapy. The current recommended dual antibiotic treatment regimen of ceftriaxone (CRO) and azithromycin (AZM) is threatened with the emergence of gonococcal strains displaying resistance to one or both of these antibiotics. Non-beta-lactamase resistance to penicillin and third-generation cephalosporins, as well as low-level AZM resistance expressed by gonococci, requires overexpression of the mtrCDE-encoded efflux pump, which in wild-type (WT) strains is subject to transcriptional repression by MtrR. Since earlier studies showed that loss of MtrCDE renders gonococci hypersusceptible to beta-lactams and macrolides, we hypothesized that transcriptional dampening of mtrCDE would render an otherwise resistant strain susceptible to these antibiotics as assessed by antibiotic susceptibility testing and during experimental infection. In order to test this hypothesis, we ectopically expressed a WT copy of the mtrR gene, which encodes the repressor of the mtrCDE efflux pump operon, in N. gonorrhoeae strain H041, the first reported gonococcal strain to cause a third-generation-cephalosporin-resistant infection. We now report that MtrR production can repress the expression of mtrCDE, increase antimicrobial susceptibility in vitro, and enhance beta-lactam efficacy in eliminating gonococci as assessed in a female mouse model of lower genital tract infection. We propose that strategies that target the MtrCDE efflux pump should be considered to counteract the increasing problem of antibiotic-resistant gonococci. IMPORTANCE The emergence of gonococcal strains resistant to past or currently used antibiotics is a global public health concern, given the estimated 78 million infections that occur annually. The dearth of new antibiotics to treat gonorrhea demands that alternative curative strategies be considered to counteract antibiotic resistance expressed by gonococci. Herein, we show that decreased expression of a drug efflux pump that participates in gonococcal resistance to antibiotics can increase gonococcal susceptibility to beta-lactams and macrolides under laboratory conditions, as well as improve antibiotic-mediated clearance of gonococci from the genital tract of experimentally infected female mice.
format	article
author	Shaochun Chen Kristie L. Connolly Corinne Rouquette-Loughlin Alexander D’Andrea Ann E. Jerse William M. Shafer
author_facet	Shaochun Chen Kristie L. Connolly Corinne Rouquette-Loughlin Alexander D’Andrea Ann E. Jerse William M. Shafer
author_sort	Shaochun Chen
title	Could Dampening Expression of the <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> <italic toggle="yes">mtrCDE</italic>-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?
title_short	Could Dampening Expression of the <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> <italic toggle="yes">mtrCDE</italic>-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?
title_full	Could Dampening Expression of the <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> <italic toggle="yes">mtrCDE</italic>-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?
title_fullStr	Could Dampening Expression of the <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> <italic toggle="yes">mtrCDE</italic>-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?
title_full_unstemmed	Could Dampening Expression of the <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> <italic toggle="yes">mtrCDE</italic>-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?
title_sort	could dampening expression of the <named-content content-type="genus-species">neisseria gonorrhoeae</named-content> <italic toggle="yes">mtrcde</italic>-encoded efflux pump be a strategy to preserve currently or resurrect formerly used antibiotics to treat gonorrhea?
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/9ae04b887f90467b992a0deffeba228d
work_keys_str_mv	AT shaochunchen coulddampeningexpressionofthenamedcontentcontenttypegenusspeciesneisseriagonorrhoeaenamedcontentitalictoggleyesmtrcdeitalicencodedeffluxpumpbeastrategytopreservecurrentlyorresurrectformerlyusedantibioticstotreatgonorrhea AT kristielconnolly coulddampeningexpressionofthenamedcontentcontenttypegenusspeciesneisseriagonorrhoeaenamedcontentitalictoggleyesmtrcdeitalicencodedeffluxpumpbeastrategytopreservecurrentlyorresurrectformerlyusedantibioticstotreatgonorrhea AT corinnerouquetteloughlin coulddampeningexpressionofthenamedcontentcontenttypegenusspeciesneisseriagonorrhoeaenamedcontentitalictoggleyesmtrcdeitalicencodedeffluxpumpbeastrategytopreservecurrentlyorresurrectformerlyusedantibioticstotreatgonorrhea AT alexanderdandrea coulddampeningexpressionofthenamedcontentcontenttypegenusspeciesneisseriagonorrhoeaenamedcontentitalictoggleyesmtrcdeitalicencodedeffluxpumpbeastrategytopreservecurrentlyorresurrectformerlyusedantibioticstotreatgonorrhea AT annejerse coulddampeningexpressionofthenamedcontentcontenttypegenusspeciesneisseriagonorrhoeaenamedcontentitalictoggleyesmtrcdeitalicencodedeffluxpumpbeastrategytopreservecurrentlyorresurrectformerlyusedantibioticstotreatgonorrhea AT williammshafer coulddampeningexpressionofthenamedcontentcontenttypegenusspeciesneisseriagonorrhoeaenamedcontentitalictoggleyesmtrcdeitalicencodedeffluxpumpbeastrategytopreservecurrentlyorresurrectformerlyusedantibioticstotreatgonorrhea
_version_	1718426919615070208

Could Dampening Expression of the <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content> <italic toggle="yes">mtrCDE</italic>-Encoded Efflux Pump Be a Strategy To Preserve Currently or Resurrect Formerly Used Antibiotics To Treat Gonorrhea?

Ejemplares similares