Genomic analysis identifies novel Pseudomonas aeruginosa resistance genes under selection during inhaled aztreonam therapy in vivo.

Genomic analysis identifies novel Pseudomonas aeruginosa resistance genes under selection during inhaled aztreonam therapy in vivo. Antimicrob Agents Chemother. 2019 Jul 08;: Authors: McLean K, Lee D, Holmes EA, Penewit K, Waalkes A, Ren M, Lee SA, Gasper J, Manoil C, Salipante SJ Abstract Inhaled aztreonam is increasingly used for chronic Pseudomonas aeruginosa suppression in patients with cystic fibrosis, but the potential for that organism to evolve aztreonam resistance remains incompletely explored. Here we performed genomic analysis of clonally related pre- and post-treatment clinical isolate pairs to identify genes that are under positive selection during aztreonam therapy in vivo We identified 16 frequently mutated genes associated with aztreonam resistance, the most prevalent being ftsI and ampC, 13 of which increased aztreonam resistance when introduced as single gene transposon mutants. Several previously implicated aztreonam resistance genes were found to be under positive selection in clinical isolates even in the absence of inhaled aztreonam exposure, indicating that other selective pressures in the CF airway can promote aztreonam resistance. Given its potential to confer plasmid-mediated resistance, we further characterized mutant ampC alleles and performed artificial evolution of ampC for maximal activity against aztreonam. We found that naturally occurring ampC mutants could confer variably increased resistance to azt...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research