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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 8906 |
| Tidsskrift | Nature Communications |
| Vol/bind | 15 |
| Udgave nummer | 1 |
| Antal sider | 14 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:We thank the Infection Microbiology group for their insightful comments and discussion. The \u2018CF Ribosome Mutation Project\u2019 was initiated by S\u00F8ren Molin, Rasmus Marvig (Rigshospitalet, Copenhagen) and Ada Yonath (Weizmann Institute, Rehovot, Israel). Special thanks to Rasmus Marvig for his detailed bioinformatic analyses of hundreds of genomes of clinical isolates of P. aeruginosa. We also thank Victor Mora for performing the preliminary ALI infections. The Basal Cell Immortalized Non-Smoker 1.1 (BCi-NS1.1) cell line was a kind gift from Professor Ronald G. Cristal (Weil Cornell Medical College, New York, USA). This research was funded by the \u201CCystic Fibrosis Trust\u201D, Strategic Research Centre Award\u20142019\u2014SRC 017, by the \u201CNovo Nordisk Foundation Center for Biosustainability (CfB)\u201D grant number NNF10CC1016517 and by the Independent Research Fund Denmark/Natural Sciences (9040-00106B). H.K.J. was supported by a clinical research stipend (NNF12OC1015920), a research grant (NNF18OC0052776), and a Challenge Grant NNF19OC0056411 from The Novo Nordisk Foundation. P.L. is the recipient of an ERS/EU RESPIRE4 Marie Sk\u0142odowska-Curie Postdoctoral Research Fellowship (Ref. nr: R4202305-01047; this project has received funding from the European Respiratory Society and the European Union\u2019s H2020 research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement No 847462).
Publisher Copyright:
© The Author(s) 2024.