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Mutation of PA4292 in Pseudomonas aeruginosa Increases β-Lactam Resistance through Upregulating Pyocyanin Production

Metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa is increasingly reported worldwide and usually causes infections with high mortality rates. Aztreonam/avibactam is a β-lactam/β-lactamase inhibitor (BLBLI) combination that is under clinical trials. ABSTRACT Metallo-β-lactamase (MBL)-producing Pseudomonas aeruginosa is increasingly reported worldwide and usually causes infections with high mortality rates. Aztreonam/avibactam is a β-lactam/β-lactamase inhibitor (BLBLI) combination that is under clinical trials. The advantage of aztreonam/avibactam over the currently used BLBLIs lies in its effectiveness against MBL-producing pathogens, making it one of the few drugs that can be used to treat infections caused by MBL-producing P. aeruginosa. However, the molecular mechanisms underlying aztreonam/avibactam resistance development remain unexplored. Here, in this study, we performed an in vitro evolution assay by using a previously identified MBL-producing P. aeruginosa clinical isolate, NKPa-71, and found mutations in a novel gene, PA4292, in the aztreonam/avibactam-resistant mutants. By mutation of PA4292 in the reference strain PA14, we verified the role of PA4292 in the resistance to aztreonam/avibactam and β-lactams. Transcriptomic analyses revealed upregulation of pyocyanin biosynthesis genes among the most overexpressed in the PA4292 mutant. We further demonstrated that pyocyanin overproduction in the PA4292 mutant increased the bacterial resistance to β-lactams by reducing drug influx. These data revealed a novel mechanism that might lead to the development of resistance to aztreonam/avibactam and β-lactams.