The following is the summary of “Macrolide therapy in Pseudomonas aeruginosa infections causes uL4 ribosomal protein mutations leading to high-level resistance” published in the December 2022 issue of Clinical microbiology and infections by Goltermann, et al.
Chronic bacterial lung infections are caused by Pseudomonas aeruginosa colonization of the airways in CF. Macrolides are the standard treatment for cystic fibrosis (CF), but P. aeruginosa is now thought to be resistant because of insufficient susceptibility testing, which has entirely obscured the mechanisms underlying this resistance. In this study, researchers looked into a novel mechanism of macrolide resistance due to mutations in the ribosomal protein. By analyzing 5,758 protein sequences from various sources and studying a longitudinal collection of 529 isolates from CF patients, alterations in P. aeruginosa‘s ribosomal proteins related to macrolide resistance were discovered.
Isolates carrying the uL4 ribosomal protein mutation were examined for resistance to macrolide antibiotics and macrolide-induced quorum sensing modulation using a modified susceptibility testing technique. The effects of the alterations on bacterial physiology were evaluated using proteome and ribosome profiling. There were 5 different uL4 mutations found in patient isolates. Most of these mutations led to improved macrolide tolerance (>10-fold relative to wt strains) and corresponded to the conserved loop region of uL4. Growth inhibition, decreased swimming motility, and induction of redox sensitivity in uL4 mutants required macrolide antibiotic doses greater than 10-fold above those used in the original study.
Due to the uL4 mutations, the ribosome stoichiometry was altered without compromising bacterial physiology, however, the expression of 16 proteins essential in ribosome adaptation was affected. Therefore, macrolide antibiotics should be recognized as active antimicrobial agents against P. aeruginosa, and resistance development should be considered when patients are treated with prolonged courses of macrolides. Enhanced macrolide susceptibility testing is crucial for identifying microorganisms that have developed resistance.
Source: sciencedirect.com/science/article/pii/S1198743X22004190
