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Antimicrob Agents Chemother. 2017 Feb 23;61(3). pii: e02188-16. doi: 10.1128/AAC.02188-16. Print 2017 Mar.

Ribosomal Mutations Conferring Macrolide Resistance in Legionella pneumophila.

Descours G1,2,3,4, Ginevra C5,2,3,4, Jacotin N4, Forey F4, Chastang J4, Kay E5,2,3, Etienne J2,3,4, Lina G2,3,4, Doublet P5,2,3, Jarraud S5,2,3,4.

Author information

1
CIRI, Centre International de Recherche en Infectiologie, Equipe Pathogénèse des Légionelles, Lyon, France ghislaine.descours@univ-lyon1.fr.
2
Inserm, U1111, Université Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Lyon, France.
3
Univ Lyon, F-69007, Lyon, France.
4
Hospices Civils de Lyon, Groupement Hospitalier Nord, National Reference Centre of Legionella, Institute for Infectious Agents, Lyon, France.
5
CIRI, Centre International de Recherche en Infectiologie, Equipe Pathogénèse des Légionelles, Lyon, France.

Abstract

Monitoring the emergence of antibiotic resistance is a recent issue in the treatment of Legionnaires' disease. Macrolides are recommended as first-line therapy, but resistance mechanisms have not been studied in Legionella species. Our aim was to determine the molecular basis of macrolide resistance in L. pneumophila Twelve independent lineages from a common susceptible L. pneumophila ancestral strain were propagated under conditions of erythromycin or azithromycin pressure to produce high-level macrolide resistance. Whole-genome sequencing was performed on 12 selected clones, and we investigated mutations common to all lineages. We reconstructed the dynamics of mutation for each lineage and demonstrated their involvement in decreased susceptibility to macrolides. The resistant mutants were produced in a limited number of passages to obtain a 4,096-fold increase in erythromycin MICs. Mutations affected highly conserved 5-amino-acid regions of L4 and L22 ribosomal proteins and of domain V of 23S rRNA (G2057, A2058, A2059, and C2611 nucleotides). The early mechanisms mainly affected L4 and L22 proteins and induced a 32-fold increase in the MICs of the selector drug. Additional mutations related to 23S rRNA mostly occurred later and were responsible for a major increase of macrolide MICs, depending on the mutated nucleotide, the substitution, and the number of mutated genes among the three rrl copies. The major mechanisms of the decreased susceptibility to macrolides in L. pneumophila and their dynamics were determined. The results showed that macrolide resistance could be easily selected in L. pneumophila and warrant further investigations in both clinical and environmental settings.

KEYWORDS:

23S rRNA; Legionella pneumophila; macrolide; resistance; ribosomal mutations; ribosomal proteins

PMID:
28069647
PMCID:
PMC5328525
DOI:
10.1128/AAC.02188-16
[Indexed for MEDLINE]
Free PMC Article

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