Azithromycin Resistance through Interspecific Acquisition of an Epistasis-Dependent Efflux Pump Component and Transcriptional Regulator in <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>

ABSTRACT Mosaic interspecifically acquired alleles of the multiple transferable resistance (mtr) efflux pump operon correlate with increased resistance to azithromycin in Neisseria gonorrhoeae in epidemiological studies. However, whether and how these alleles cause resistance is unclear. Here, we us...

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Autores principales:	Crista B. Wadsworth, Brian J. Arnold, Mohamad R. Abdul Sater, Yonatan H. Grad
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Neisseria gonorrhoeae antibiotic resistance efflux pump epistasis gonorrhea macrolide Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7f85e726355b4edf8b9c7ddde05404ad
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spelling	oai:doaj.org-article:7f85e726355b4edf8b9c7ddde05404ad2021-11-15T16:00:15ZAzithromycin Resistance through Interspecific Acquisition of an Epistasis-Dependent Efflux Pump Component and Transcriptional Regulator in <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>10.1128/mBio.01419-182150-7511https://doaj.org/article/7f85e726355b4edf8b9c7ddde05404ad2018-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01419-18https://doaj.org/toc/2150-7511ABSTRACT Mosaic interspecifically acquired alleles of the multiple transferable resistance (mtr) efflux pump operon correlate with increased resistance to azithromycin in Neisseria gonorrhoeae in epidemiological studies. However, whether and how these alleles cause resistance is unclear. Here, we use population genomics, transformations, and transcriptional analyses to dissect the relationship between variant mtr alleles and azithromycin resistance. We find that the locus encompassing the mtrR transcriptional repressor and the mtrCDE pump is a hot spot of interspecific recombination introducing alleles from Neisseria meningitidis and Neisseria lactamica into N. gonorrhoeae, with multiple rare haplotypes in linkage disequilibrium at mtrD and the mtr promoter region. Transformations demonstrate that resistance to azithromycin, as well as to other antimicrobial compounds such as polymyxin B and crystal violet, is mediated through epistasis between these two loci and that the full-length mosaic mtrD allele is required. Gene expression profiling reveals the mechanism of resistance in mosaics couples novel mtrD alleles with promoter mutations that increase expression of the pump. Overall, our results demonstrate that epistatic interactions at mtr gained from multiple neisserial species has contributed to increased gonococcal resistance to diverse antimicrobial agents. IMPORTANCE Neisseria gonorrhoeae is the sexually transmitted bacterial pathogen responsible for more than 100 million cases of gonorrhea worldwide each year. The incidence of resistance to the macrolide azithromycin has increased in the past decade; however, a large proportion of the genetic basis of resistance remains unexplained. This study is the first to conclusively demonstrate the acquisition of macrolide resistance through mtr alleles from other Neisseria species, demonstrating that commensal Neisseria bacteria are a reservoir for antibiotic resistance to macrolides, extending the role of interspecies mosaicism in resistance beyond what has been previously described for cephalosporins. Ultimately, our results emphasize that future fine-mapping of genome-wide interspecies mosaicism may be valuable in understanding the pathways to antimicrobial resistance. Our results also have implications for diagnostics and public health surveillance and control, as they can be used to inform the development of sequence-based tools to monitor and control the spread of antibiotic-resistant gonorrhea.Crista B. WadsworthBrian J. ArnoldMohamad R. Abdul SaterYonatan H. GradAmerican Society for MicrobiologyarticleNeisseria gonorrhoeaeantibiotic resistanceefflux pumpepistasisgonorrheamacrolideMicrobiologyQR1-502ENmBio, Vol 9, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neisseria gonorrhoeae antibiotic resistance efflux pump epistasis gonorrhea macrolide Microbiology QR1-502
spellingShingle	Neisseria gonorrhoeae antibiotic resistance efflux pump epistasis gonorrhea macrolide Microbiology QR1-502 Crista B. Wadsworth Brian J. Arnold Mohamad R. Abdul Sater Yonatan H. Grad Azithromycin Resistance through Interspecific Acquisition of an Epistasis-Dependent Efflux Pump Component and Transcriptional Regulator in <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
description	ABSTRACT Mosaic interspecifically acquired alleles of the multiple transferable resistance (mtr) efflux pump operon correlate with increased resistance to azithromycin in Neisseria gonorrhoeae in epidemiological studies. However, whether and how these alleles cause resistance is unclear. Here, we use population genomics, transformations, and transcriptional analyses to dissect the relationship between variant mtr alleles and azithromycin resistance. We find that the locus encompassing the mtrR transcriptional repressor and the mtrCDE pump is a hot spot of interspecific recombination introducing alleles from Neisseria meningitidis and Neisseria lactamica into N. gonorrhoeae, with multiple rare haplotypes in linkage disequilibrium at mtrD and the mtr promoter region. Transformations demonstrate that resistance to azithromycin, as well as to other antimicrobial compounds such as polymyxin B and crystal violet, is mediated through epistasis between these two loci and that the full-length mosaic mtrD allele is required. Gene expression profiling reveals the mechanism of resistance in mosaics couples novel mtrD alleles with promoter mutations that increase expression of the pump. Overall, our results demonstrate that epistatic interactions at mtr gained from multiple neisserial species has contributed to increased gonococcal resistance to diverse antimicrobial agents. IMPORTANCE Neisseria gonorrhoeae is the sexually transmitted bacterial pathogen responsible for more than 100 million cases of gonorrhea worldwide each year. The incidence of resistance to the macrolide azithromycin has increased in the past decade; however, a large proportion of the genetic basis of resistance remains unexplained. This study is the first to conclusively demonstrate the acquisition of macrolide resistance through mtr alleles from other Neisseria species, demonstrating that commensal Neisseria bacteria are a reservoir for antibiotic resistance to macrolides, extending the role of interspecies mosaicism in resistance beyond what has been previously described for cephalosporins. Ultimately, our results emphasize that future fine-mapping of genome-wide interspecies mosaicism may be valuable in understanding the pathways to antimicrobial resistance. Our results also have implications for diagnostics and public health surveillance and control, as they can be used to inform the development of sequence-based tools to monitor and control the spread of antibiotic-resistant gonorrhea.
format	article
author	Crista B. Wadsworth Brian J. Arnold Mohamad R. Abdul Sater Yonatan H. Grad
author_facet	Crista B. Wadsworth Brian J. Arnold Mohamad R. Abdul Sater Yonatan H. Grad
author_sort	Crista B. Wadsworth
title	Azithromycin Resistance through Interspecific Acquisition of an Epistasis-Dependent Efflux Pump Component and Transcriptional Regulator in <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
title_short	Azithromycin Resistance through Interspecific Acquisition of an Epistasis-Dependent Efflux Pump Component and Transcriptional Regulator in <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
title_full	Azithromycin Resistance through Interspecific Acquisition of an Epistasis-Dependent Efflux Pump Component and Transcriptional Regulator in <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
title_fullStr	Azithromycin Resistance through Interspecific Acquisition of an Epistasis-Dependent Efflux Pump Component and Transcriptional Regulator in <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
title_full_unstemmed	Azithromycin Resistance through Interspecific Acquisition of an Epistasis-Dependent Efflux Pump Component and Transcriptional Regulator in <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>
title_sort	azithromycin resistance through interspecific acquisition of an epistasis-dependent efflux pump component and transcriptional regulator in <named-content content-type="genus-species">neisseria gonorrhoeae</named-content>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/7f85e726355b4edf8b9c7ddde05404ad
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Azithromycin Resistance through Interspecific Acquisition of an Epistasis-Dependent Efflux Pump Component and Transcriptional Regulator in <named-content content-type="genus-species">Neisseria gonorrhoeae</named-content>

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