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A Single Amino Acid Substitution in Elongation Factor G Can Confer Low-Level Gentamicin Resistance in Neisseria gonorrhoeae

The continued emergence of Neisseria gonorrhoeae isolates which are resistant to first-line antibiotics has reinvigorated interest in alternative therapies such as expanded use of gentamicin (Gen). We hypothesized that expanded use of Gen promotes emergence of gonococci with clinical resistance to t...

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Autores principales: Holley, Concerta L., Dhulipala, Vijaya, Balthazar, Jacqueline T., Le Van, Adriana, Begum, Afrin A., Chen, Shao-Chun, Read, Timothy D., Matoga, Mitch, Hoffman, Irving F., Golparian, Daniel, Unemo, Magnus, Jerse, Ann E., 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/PMC9112995/
https://www.ncbi.nlm.nih.gov/pubmed/35465683
http://dx.doi.org/10.1128/aac.00251-22
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author Holley, Concerta L.
Dhulipala, Vijaya
Balthazar, Jacqueline T.
Le Van, Adriana
Begum, Afrin A.
Chen, Shao-Chun
Read, Timothy D.
Matoga, Mitch
Hoffman, Irving F.
Golparian, Daniel
Unemo, Magnus
Jerse, Ann E.
Shafer, William M.
author_facet Holley, Concerta L.
Dhulipala, Vijaya
Balthazar, Jacqueline T.
Le Van, Adriana
Begum, Afrin A.
Chen, Shao-Chun
Read, Timothy D.
Matoga, Mitch
Hoffman, Irving F.
Golparian, Daniel
Unemo, Magnus
Jerse, Ann E.
Shafer, William M.
author_sort Holley, Concerta L.
collection PubMed
description The continued emergence of Neisseria gonorrhoeae isolates which are resistant to first-line antibiotics has reinvigorated interest in alternative therapies such as expanded use of gentamicin (Gen). We hypothesized that expanded use of Gen promotes emergence of gonococci with clinical resistance to this aminoglycoside. To understand how decreased susceptibility of gonococci to Gen might develop, we selected spontaneous low-level Gen-resistant (Gen(R)) mutants (Gen MIC = 32 μg/mL) of the Gen-susceptible strain FA19. Consequently, we identified a novel missense mutation in fusA, which encodes elongation factor G (EF-G), causing an alanine (A) to valine (V) substitution at amino acid position 563 in domain IV of EF-G; the mutant allele was termed fusA2. Transformation analysis showed that fusA2 could increase the Gen MIC by 4-fold. While possession of fusA2 did not impair either in vitro gonococcal growth or protein synthesis, it did result in a fitness defect during experimental infection of the lower genital tract in female mice. Through bioinformatic analysis of whole-genome sequences of 10,634 international gonococcal clinical isolates, other fusA alleles were frequently detected, but genetic studies revealed that they could not decrease Gen susceptibility in a similar manner to fusA2. In contrast to these diverse international fusA alleles, the fusA2-encoded A563V substitution was detected in only a single gonococcal clinical isolate. We hypothesize that the rare occurrence of fusA2 in N. gonorrhoeae clinical isolates is likely due to a fitness cost during infection, but compensatory mutations which alleviate this fitness cost could emerge and promote Gen(R) in global strains.
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spelling pubmed-91129952022-05-18 A Single Amino Acid Substitution in Elongation Factor G Can Confer Low-Level Gentamicin Resistance in Neisseria gonorrhoeae Holley, Concerta L. Dhulipala, Vijaya Balthazar, Jacqueline T. Le Van, Adriana Begum, Afrin A. Chen, Shao-Chun Read, Timothy D. Matoga, Mitch Hoffman, Irving F. Golparian, Daniel Unemo, Magnus Jerse, Ann E. Shafer, William M. Antimicrob Agents Chemother Mechanisms of Resistance The continued emergence of Neisseria gonorrhoeae isolates which are resistant to first-line antibiotics has reinvigorated interest in alternative therapies such as expanded use of gentamicin (Gen). We hypothesized that expanded use of Gen promotes emergence of gonococci with clinical resistance to this aminoglycoside. To understand how decreased susceptibility of gonococci to Gen might develop, we selected spontaneous low-level Gen-resistant (Gen(R)) mutants (Gen MIC = 32 μg/mL) of the Gen-susceptible strain FA19. Consequently, we identified a novel missense mutation in fusA, which encodes elongation factor G (EF-G), causing an alanine (A) to valine (V) substitution at amino acid position 563 in domain IV of EF-G; the mutant allele was termed fusA2. Transformation analysis showed that fusA2 could increase the Gen MIC by 4-fold. While possession of fusA2 did not impair either in vitro gonococcal growth or protein synthesis, it did result in a fitness defect during experimental infection of the lower genital tract in female mice. Through bioinformatic analysis of whole-genome sequences of 10,634 international gonococcal clinical isolates, other fusA alleles were frequently detected, but genetic studies revealed that they could not decrease Gen susceptibility in a similar manner to fusA2. In contrast to these diverse international fusA alleles, the fusA2-encoded A563V substitution was detected in only a single gonococcal clinical isolate. We hypothesize that the rare occurrence of fusA2 in N. gonorrhoeae clinical isolates is likely due to a fitness cost during infection, but compensatory mutations which alleviate this fitness cost could emerge and promote Gen(R) in global strains. American Society for Microbiology 2022-04-25 /pmc/articles/PMC9112995/ /pubmed/35465683 http://dx.doi.org/10.1128/aac.00251-22 Text en Copyright © 2022 Holley et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Mechanisms of Resistance
Holley, Concerta L.
Dhulipala, Vijaya
Balthazar, Jacqueline T.
Le Van, Adriana
Begum, Afrin A.
Chen, Shao-Chun
Read, Timothy D.
Matoga, Mitch
Hoffman, Irving F.
Golparian, Daniel
Unemo, Magnus
Jerse, Ann E.
Shafer, William M.
A Single Amino Acid Substitution in Elongation Factor G Can Confer Low-Level Gentamicin Resistance in Neisseria gonorrhoeae
title A Single Amino Acid Substitution in Elongation Factor G Can Confer Low-Level Gentamicin Resistance in Neisseria gonorrhoeae
title_full A Single Amino Acid Substitution in Elongation Factor G Can Confer Low-Level Gentamicin Resistance in Neisseria gonorrhoeae
title_fullStr A Single Amino Acid Substitution in Elongation Factor G Can Confer Low-Level Gentamicin Resistance in Neisseria gonorrhoeae
title_full_unstemmed A Single Amino Acid Substitution in Elongation Factor G Can Confer Low-Level Gentamicin Resistance in Neisseria gonorrhoeae
title_short A Single Amino Acid Substitution in Elongation Factor G Can Confer Low-Level Gentamicin Resistance in Neisseria gonorrhoeae
title_sort single amino acid substitution in elongation factor g can confer low-level gentamicin resistance in neisseria gonorrhoeae
topic Mechanisms of Resistance
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9112995/
https://www.ncbi.nlm.nih.gov/pubmed/35465683
http://dx.doi.org/10.1128/aac.00251-22
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