C yclic‐di‐ GMP levels affect P seudomonas aeruginosa fitness in the presence of imipenem

Summary A large number of genes coding for enzymes predicted to synthesize and degrade 3′–5′‐cyclic diguanylic acid (c‐di‐ GMP ) is found in most bacterial genomes and this dinucleotide emerged as an intracellular signal‐controlling bacterial behaviour. An association between high levels of c‐di‐ GMP and antibiotic resistance may be expected because c‐di‐ GMP regulates biofilm formation and this mode of growth leads to enhanced antibiotic resistance. However, a clear understanding of this correlation has not been established. We found that increased levels of c‐di‐ GMP in P seudomonas aeruginosa improve fitness in the presence of imipenem, even when grown as planktonic cells. P . aeruginosa post‐transcriptionally regulates the amounts of five porins in response to c‐di‐ GMP , including OprD , responsible for imipenem uptake. Cells with low c‐di‐ GMP levels are consequently more sensitive to this antibiotic. Main efflux pumps or β‐lactamase genes did not show altered mRNA levels in P . aeruginosa strains with modified different c‐di‐ GMP concentrations. Together, our findings show that c‐di‐ GMP levels modulate fitness of planktonic cultures in the presence of imipenem.