BatR: A novel regulator of antibiotic tolerance inPseudomonas aeruginosabiofilms

Abstract

ABSTRACTPseudomonas aeruginosais a multidrug-resistant opportunistic human pathogen. Chronic infections are associated with biofilms, conferring resistance to antibiotics and complicating treatment strategies. This study focuses on understanding the role of the uncharacterized genePA3049, upregulated under biofilm conditions. In the context ofP. aeruginosabiofilms,PA3049plays a role in withstanding antimicrobial challenges bothin vitroand in clinically validated infection models. Under sub-inhibitory concentrations of antibiotic, the deletion ofPA3049resulted in reduced pyocyanin production and altered abundance of enzymes controlling denitrification, pyoverdine, and hydrogen cyanide biosynthesis. Notably, PA3049 directly interacts with two kinases implicated in stress response, inactivating their active sites. Renamed as theBiofilmantibiotic toleranceRegulator (BatR), PA3049 is a key player inP. aeruginosabiofilm maintenance and antimicrobial tolerance. These findings contribute to understanding the complex bacterial lifestyle in biofilms, shedding light on a previously uncharacterized gene with significant implications for combating multidrug-resistant infections.IMPORTANCEP. aeruginosais a multidrug-resistant ESKAPE pathogen that causes chronic biofilm-based infections and is a leading cause of mortality in cystic fibrosis (CF) patients. Understanding the molecular mechanisms underlyingP. aeruginosabiofilm resilience and antimicrobial resistance is crucial for developing effective therapeutic interventions. This study focuses on characterizing the genePA3049, now known as thebiofilmantibiotic toleranceRegulator(batR). BatR plays a central role withinP. aeruginosabiofilms, orchestrating adaptive responses to antimicrobial challenges. Our work sheds light on the contribution ofbatRto biofilm biology and its relevance in lung infections, where subinhibitory antibiotic concentrations make BatR pivotal for bacterial survival. By advancing our understanding ofP. aeruginosabiofilm regulation, this study holds significant promise for the development of innovative approaches against biofilm-associated infections to mitigate the growing threat of antimicrobial resistance.