Macrolide resistance through uL4 and uL22 ribosomal mutations inPseudomonas aeruginosa

Abstract

AbstractMacrolides are widely used antibiotics for the treatment of bacterial airway infections. Due to its elevated minimum inhibitory concentration in standardized culture media,Pseudomonas aeruginosais 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 persistentP. aeruginosainfections. Here, we demonstrate that macrolides are, instead, effective antibiotics againstP. aeruginosaairway 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 inP. aeruginosawhich 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 asde factoantibiotics againstP. aeruginosaand the need for resistance monitoring upon prolonged macrolide treatment.