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Gonococcal Clinical Strains Bearing a Common gdhR Single Nucleotide Polymorphism That Results in Enhanced Expression of the Virulence Gene lctP Frequently Possess a mtrR Promoter Mutation That Decreases Antibiotic Susceptibility

GdhR is a transcriptional repressor of the virulence factor gene lctP, which encodes a unique l-lactate permease that has been linked to pathogenesis of Neisseria gonorrhoeae, and loss of gdhR can confer increased fitness of gonococci in a female mouse model of lower genital tract infection. In this...

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Autores principales: Ayala, Julio C., Schmerer, Matthew W., Kersh, Ellen N., Unemo, Magnus, Shafer, William M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9040798/
https://www.ncbi.nlm.nih.gov/pubmed/35258329
http://dx.doi.org/10.1128/mbio.00276-22
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author Ayala, Julio C.
Schmerer, Matthew W.
Kersh, Ellen N.
Unemo, Magnus
Shafer, William M.
author_facet Ayala, Julio C.
Schmerer, Matthew W.
Kersh, Ellen N.
Unemo, Magnus
Shafer, William M.
author_sort Ayala, Julio C.
collection PubMed
description GdhR is a transcriptional repressor of the virulence factor gene lctP, which encodes a unique l-lactate permease that has been linked to pathogenesis of Neisseria gonorrhoeae, and loss of gdhR can confer increased fitness of gonococci in a female mouse model of lower genital tract infection. In this work, we identified a single nucleotide polymorphism (SNP) in gdhR, which is often present in both recent and historical gonococcal clinical strains and results in a proline (P)-to-serine (S) change at amino acid position 6 (P6S) of GdhR. This mutation (gdhR6) was found to reduce GdhR transcriptional repression at lctP in gonococcal strains containing the mutant protein compared to wild-type GdhR. By using purified recombinant proteins and in vitro DNA-binding and cross-linking experiments, we found that gdhR6 impairs the DNA-binding activity of GdhR at lctP without an apparent effect on protein oligomerization. By analyzing a panel of U.S. (from 2017 to 2018) and Danish (1928 to 2013) clinical isolates, we observed a statistical association between gdhR6 and the previously described adenine deletion in the promoter of mtrR (mtrR-P A-del), encoding the repressor (MtrR) of the mtrCDE operon that encodes the MtrCDE multidrug efflux pump that can export antibiotics, host antimicrobials, and biocides. The frequent association of gdhR6 with the mtrR promoter mutation in these clinical isolates suggests that it has persisted in this genetic background to enhance lctP expression, thereby promoting virulence.
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spelling pubmed-90407982022-04-27 Gonococcal Clinical Strains Bearing a Common gdhR Single Nucleotide Polymorphism That Results in Enhanced Expression of the Virulence Gene lctP Frequently Possess a mtrR Promoter Mutation That Decreases Antibiotic Susceptibility Ayala, Julio C. Schmerer, Matthew W. Kersh, Ellen N. Unemo, Magnus Shafer, William M. mBio Research Article GdhR is a transcriptional repressor of the virulence factor gene lctP, which encodes a unique l-lactate permease that has been linked to pathogenesis of Neisseria gonorrhoeae, and loss of gdhR can confer increased fitness of gonococci in a female mouse model of lower genital tract infection. In this work, we identified a single nucleotide polymorphism (SNP) in gdhR, which is often present in both recent and historical gonococcal clinical strains and results in a proline (P)-to-serine (S) change at amino acid position 6 (P6S) of GdhR. This mutation (gdhR6) was found to reduce GdhR transcriptional repression at lctP in gonococcal strains containing the mutant protein compared to wild-type GdhR. By using purified recombinant proteins and in vitro DNA-binding and cross-linking experiments, we found that gdhR6 impairs the DNA-binding activity of GdhR at lctP without an apparent effect on protein oligomerization. By analyzing a panel of U.S. (from 2017 to 2018) and Danish (1928 to 2013) clinical isolates, we observed a statistical association between gdhR6 and the previously described adenine deletion in the promoter of mtrR (mtrR-P A-del), encoding the repressor (MtrR) of the mtrCDE operon that encodes the MtrCDE multidrug efflux pump that can export antibiotics, host antimicrobials, and biocides. The frequent association of gdhR6 with the mtrR promoter mutation in these clinical isolates suggests that it has persisted in this genetic background to enhance lctP expression, thereby promoting virulence. American Society for Microbiology 2022-03-08 /pmc/articles/PMC9040798/ /pubmed/35258329 http://dx.doi.org/10.1128/mbio.00276-22 Text en https://doi.org/10.1128/AuthorWarrantyLicense.v1This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.
spellingShingle Research Article
Ayala, Julio C.
Schmerer, Matthew W.
Kersh, Ellen N.
Unemo, Magnus
Shafer, William M.
Gonococcal Clinical Strains Bearing a Common gdhR Single Nucleotide Polymorphism That Results in Enhanced Expression of the Virulence Gene lctP Frequently Possess a mtrR Promoter Mutation That Decreases Antibiotic Susceptibility
title Gonococcal Clinical Strains Bearing a Common gdhR Single Nucleotide Polymorphism That Results in Enhanced Expression of the Virulence Gene lctP Frequently Possess a mtrR Promoter Mutation That Decreases Antibiotic Susceptibility
title_full Gonococcal Clinical Strains Bearing a Common gdhR Single Nucleotide Polymorphism That Results in Enhanced Expression of the Virulence Gene lctP Frequently Possess a mtrR Promoter Mutation That Decreases Antibiotic Susceptibility
title_fullStr Gonococcal Clinical Strains Bearing a Common gdhR Single Nucleotide Polymorphism That Results in Enhanced Expression of the Virulence Gene lctP Frequently Possess a mtrR Promoter Mutation That Decreases Antibiotic Susceptibility
title_full_unstemmed Gonococcal Clinical Strains Bearing a Common gdhR Single Nucleotide Polymorphism That Results in Enhanced Expression of the Virulence Gene lctP Frequently Possess a mtrR Promoter Mutation That Decreases Antibiotic Susceptibility
title_short Gonococcal Clinical Strains Bearing a Common gdhR Single Nucleotide Polymorphism That Results in Enhanced Expression of the Virulence Gene lctP Frequently Possess a mtrR Promoter Mutation That Decreases Antibiotic Susceptibility
title_sort gonococcal clinical strains bearing a common gdhr single nucleotide polymorphism that results in enhanced expression of the virulence gene lctp frequently possess a mtrr promoter mutation that decreases antibiotic susceptibility
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9040798/
https://www.ncbi.nlm.nih.gov/pubmed/35258329
http://dx.doi.org/10.1128/mbio.00276-22
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