Macrolide resistance through uL4 and uL22 ribosomal mutations in Pseudomonas aeruginosa

Lise Goltermann, Pablo Laborda, Oihane Irazoqui, Ivan Pogrebnyakov, Maria Pals Bendixen, Søren Molin, Helle Krogh Johansen () and Ruggero La Rosa ()
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Lise Goltermann: Department of Clinical Microbiology 9301
Pablo Laborda: Department of Clinical Microbiology 9301
Oihane Irazoqui: Technical University of Denmark
Ivan Pogrebnyakov: Technical University of Denmark
Maria Pals Bendixen: Department of Clinical Microbiology 9301
Søren Molin: Technical University of Denmark
Helle Krogh Johansen: Department of Clinical Microbiology 9301
Ruggero La Rosa: Department of Clinical Microbiology 9301

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Macrolides are widely used antibiotics for the treatment of bacterial airway infections. Due to its elevated minimum inhibitory concentration in standardized culture media, Pseudomonas aeruginosa is considered intrinsically resistant and, therefore, antibiotic susceptibility testing against macrolides is not performed. Nevertheless, due to macrolides’ immunomodulatory effect and suppression of virulence factors, they are used for the treatment of persistent P. aeruginosa infections. Here, we demonstrate that macrolides are, instead, effective antibiotics against P. aeruginosa airway infections in an Air-Liquid Interface (ALI) infection model system resembling the human airways. Importantly, macrolide treatment in both people with cystic fibrosis and primary ciliary dyskinesia patients leads to the accumulation of uL4 and uL22 ribosomal protein mutations in P. aeruginosa which causes antibiotic resistance. Consequently, higher concentrations of antibiotics are needed to modulate the macrolide-dependent suppression of virulence. Surprisingly, even in the absence of antibiotics, these mutations also lead to a collateral reduction in growth rate, virulence and pathogenicity in airway ALI infections which are pivotal for the establishment of a persistent infection. Altogether, these results lend further support to the consideration of macrolides as de facto antibiotics against P. aeruginosa and the need for resistance monitoring upon prolonged macrolide treatment.

Date: 2024
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DOI: 10.1038/s41467-024-53329-8

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