Department of Clinical Microbiology 9301, Rigshospitalet, 2100, Copenhagen, Denmark.
The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800, Kgs. Lyngby, Denmark.
Nat Commun. 2024 Oct 16;15(1):8906. doi: 10.1038/s41467-024-53329-8.
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.
大环内酯类抗生素被广泛用于治疗细菌性气道感染。由于其在标准化培养介质中的最低抑菌浓度升高，铜绿假单胞菌被认为具有固有耐药性，因此，不对大环内酯类抗生素进行药敏试验。然而，由于大环内酯类药物具有免疫调节作用和抑制毒力因子的作用，它们被用于治疗持续性铜绿假单胞菌感染。在这里，我们证明在类似于人类气道的气液界面（ALI）感染模型系统中，大环内酯类药物是治疗铜绿假单胞菌气道感染的有效抗生素。重要的是，大环内酯类药物治疗囊性纤维化患者和原发性纤毛运动障碍患者会导致铜绿假单胞菌中 uL4 和 uL22 核糖体蛋白突变的积累，从而导致抗生素耐药性。因此，需要更高浓度的抗生素来调节大环内酯类药物依赖性的毒力抑制。令人惊讶的是，即使没有抗生素，这些突变也会导致气道 ALI 感染中的生长速度、毒力和致病性的附带降低，这对于持续性感染的建立至关重要。总之，这些结果进一步支持将大环内酯类药物视为铜绿假单胞菌的事实上的抗生素，并需要在长期大环内酯类药物治疗时监测耐药性。
