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Macrolides are recommended as first-line therapy, but resistance mechanisms have not been studied in<jats:named-content content-type=\"genus-species\">Legionella<\/jats:named-content>species. Our aim was to determine the molecular basis of macrolide resistance in<jats:named-content content-type=\"genus-species\">L. pneumophila<\/jats:named-content>. Twelve independent lineages from a common susceptible<jats:named-content content-type=\"genus-species\">L. pneumophila<\/jats:named-content>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<jats:italic>rrl<\/jats:italic>copies. The major mechanisms of the decreased susceptibility to macrolides in<jats:named-content content-type=\"genus-species\">L. pneumophila<\/jats:named-content>and their dynamics were determined. The results showed that macrolide resistance could be easily selected in<jats:named-content content-type=\"genus-species\">L. pneumophila<\/jats:named-content>and warrant further investigations in both clinical and environmental settings.<\/jats:p>","DOI":"10.1128\/aac.02188-16","type":"journal-article","created":{"date-parts":[[2017,1,10]],"date-time":"2017-01-10T02:30:27Z","timestamp":1484015427000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":37,"title":["Ribosomal Mutations Conferring Macrolide Resistance in Legionella pneumophila"],"prefix":"10.1128","volume":"61","author":[{"given":"Ghislaine","family":"Descours","sequence":"first","affiliation":[{"name":"CIRI, Centre International de Recherche en Infectiologie, Equipe Pathog\u00e9n\u00e8se des L\u00e9gionelles, Lyon, France"},{"name":"Inserm, U1111, Universit\u00e9 Lyon 1, CNRS, UMR5308, \u00c9cole Normale Sup\u00e9rieure de Lyon, Lyon, 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