Revealing adaptive mechanisms and antibiotic tolerance in Pseudomonas aeruginosa infections: The role of host-pathogen interactions in bacterial recalcitrance

Bacterial respiratory infections continue to pose significant global health threats, exacerbated by the rise of antibiotic resistance. While much attention has focused on antibiotic-driven resistance in bacterial pathogens, the role of bacterial interactions with the host and immune system in maintaining persistent infections remains underexplored. By employing an air-liquid interface cell culture model system designed to replicate human airway conditions, we have revealed novel adaptive mechanisms and antibiotic tolerance in Pseudomonas aeruginosa infections that extend beyond conventional antibiotic resistance. For instance, we observed that mutations in a multidrug efflux pump regulator -commonly acquired in clinical P. aeruginosa isolates during chronic lung infections- enhance bacterial invasiveness into the lung tissue, where antibiotic penetration is limited, thus providing these bacteria with protection from antibiotic action. Additionally, mutations in key metabolic enzymes of P. aeruginosa, also commonly selected in clinical settings, increase bacterial resilience to oxidative stress while also modulating host immune responses. Furthermore, we identified unexpected efficacy of macrolides against P. aeruginosa under infection conditions, challenging the prevailing notion of intrinsic macrolide resistance and prompting a re-evaluation of their role in current continuous prophylactic strategies. These findings emphasize the critical role of host-pathogen interactions in respiratory infections. Understanding these dynamics may inform the development of host-targeted therapeutic strategies to better manage this threat.