Molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae.

Anti-Bacterial Agents / pharmacology Azithromycin / pharmacology Drug Resistance, Bacterial / genetics Microbial Sensitivity Tests Mutation Neisseria gonorrhoeae / genetics RNA, Ribosomal, 23S / genetics

Journal

The Journal of antimicrobial chemotherapy
ISSN: 1460-2091
Titre abrégé: J Antimicrob Chemother
Pays: England
ID NLM: 7513617

Informations de publication

Date de publication:
18 06 2021
Historique:
received: 02 10 2020
accepted: 28 02 2021
pubmed: 25 3 2021
medline: 2 7 2021
entrez: 24 3 2021
Statut: ppublish

Résumé

The prevalence of azithromycin resistance in Neisseria gonorrhoeae is increasing in numerous populations worldwide. To characterize the genetic pathways leading to high-level azithromycin resistance. A customized morbidostat was used to subject two N. gonorrhoeae reference strains (WHO-F and WHO-X) to dynamically sustained azithromycin pressure. We tracked stepwise evolution of resistance by whole genome sequencing. Within 26 days, all cultures evolved high-level azithromycin resistance. Typically, the first step towards resistance was found in transitory mutations in genes rplD, rplV and rpmH (encoding the ribosomal proteins L4, L22 and L34 respectively), followed by mutations in the MtrCDE-encoded efflux pump and the 23S rRNA gene. Low- to high-level resistance was associated with mutations in the ribosomal proteins and MtrCDE efflux pump. However, high-level resistance was consistently associated with mutations in the 23S ribosomal RNA, mainly the well-known A2059G and C2611T mutations, but also at position A2058G. This study enabled us to track previously reported mutations and identify novel mutations in ribosomal proteins (L4, L22 and L34) that may play a role in the genesis of azithromycin resistance in N. gonorrhoeae.

Sections du résumé

BACKGROUND
The prevalence of azithromycin resistance in Neisseria gonorrhoeae is increasing in numerous populations worldwide.
OBJECTIVES
To characterize the genetic pathways leading to high-level azithromycin resistance.
METHODS
A customized morbidostat was used to subject two N. gonorrhoeae reference strains (WHO-F and WHO-X) to dynamically sustained azithromycin pressure. We tracked stepwise evolution of resistance by whole genome sequencing.
RESULTS
Within 26 days, all cultures evolved high-level azithromycin resistance. Typically, the first step towards resistance was found in transitory mutations in genes rplD, rplV and rpmH (encoding the ribosomal proteins L4, L22 and L34 respectively), followed by mutations in the MtrCDE-encoded efflux pump and the 23S rRNA gene. Low- to high-level resistance was associated with mutations in the ribosomal proteins and MtrCDE efflux pump. However, high-level resistance was consistently associated with mutations in the 23S ribosomal RNA, mainly the well-known A2059G and C2611T mutations, but also at position A2058G.
CONCLUSIONS
This study enabled us to track previously reported mutations and identify novel mutations in ribosomal proteins (L4, L22 and L34) that may play a role in the genesis of azithromycin resistance in N. gonorrhoeae.

Identifiants

DOI: 10.1093/jac/dkab084 PMID: 33760080
pubmed: 33760080
pii: 6184841
doi: 10.1093/jac/dkab084
doi:

Substances chimiques

Anti-Bacterial Agents 0
RNA, Ribosomal, 23S 0
Azithromycin 83905-01-5

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1752-1758

Informations de copyright

© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Auteurs

J G E Laumen (JGE)

Institute of Tropical Medicine, Department of Clinical Sciences, STI Unit, Antwerp, Belgium.
University of Antwerp, Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, Antwerp, Belgium.

S S Manoharan-Basil (SS)

Institute of Tropical Medicine, Department of Clinical Sciences, STI Unit, Antwerp, Belgium.

E Verhoeven (E)

Institute of Tropical Medicine, Department of Clinical Sciences, STI Unit, Antwerp, Belgium.
Pfizer, Puurs, Belgium.

S Abdellati (S)

Institute of Tropical Medicine, Department of Clinical Sciences, Clinical Reference Laboratory, Antwerp, Belgium.

I De Baetselier (I)

Institute of Tropical Medicine, Department of Clinical Sciences, Clinical Reference Laboratory, Antwerp, Belgium.

T Crucitti (T)

Centre Pasteur du Cameroun, Yaounde, Cameroon.

B B Xavier (BB)

University of Antwerp, Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, Antwerp, Belgium.

S Chapelle (S)

University of Antwerp, Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, Antwerp, Belgium.

C Lammens (C)

University of Antwerp, Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, Antwerp, Belgium.

C Van Dijck (C)

Institute of Tropical Medicine, Department of Clinical Sciences, STI Unit, Antwerp, Belgium.
University of Antwerp, Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, Antwerp, Belgium.

S Malhotra-Kumar (S)

University of Antwerp, Laboratory of Medical Microbiology, Vaccine and Infectious Disease Institute, Antwerp, Belgium.

C Kenyon (C)

Institute of Tropical Medicine, Department of Clinical Sciences, STI Unit, Antwerp, Belgium.
Department of Medicine, University of Cape Town, Cape Town, South Africa.
ORCID: 0000-0002-2557-8998

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antibactériens › Molecular pathways to high-level azithromycin...
questionsmedicales.fr › Composés chimiques organiques › Lactones › Érythromycine › Azithromycine › Molecular pathways to high-level azithromycin...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance microbienne aux médicaments › Résistance bactérienne aux médicaments › Molecular pathways to high-level azithromycin...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Tests de sensibilité microbienne › Molecular pathways to high-level azithromycin...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Molecular pathways to high-level azithromycin...
questionsmedicales.fr › Bactéries › Proteobacteria › Betaproteobacteria › Neisseriaceae › Neisseria › Neisseria gonorrhoeae › Molecular pathways to high-level azithromycin...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN ribosomique › ARN ribosomique 23S › Molecular pathways to high-level azithromycin...