Harnessing Light to Control Bacterial Adhesion: A New Frontier in the Fight Against AMR

Antimicrobial resistance (AMR) represents a growing global health threat, particularly in the context of healthcare-associated infections. A major factor contributing to the persistence and dissemination of AMR is the formation of microbial biofilms, which provide a protective microenvironment that enhances survival and promotes horizontal gene transfer. Central to biofilm development are bacterial adhesion proteins, which mediate crucial interactions between microbial cells and surfaces, thereby facilitating the establishment of highly resistant microbial communities. Owing to their pivotal role in biofilm formation, adhesion proteins have emerged as promising molecular targets for the development of novel anti-AMR strategies. Among these, the virulence factor LecB—a lectin located on the outer membrane of Pseudomonas aeruginosa—plays a key role in pathogen persistence and virulence in clinical settings. LecB exhibits strong carbohydrate-binding activity, mediating interactions with both the bacterial outer membrane and exopolysaccharides within the biofilm matrix and has thus attracted considerable attention as a potential antibiofilm drug target. This study focuses on the identification and development of innovative photoswitchable ligands capable of binding to and modulating LecB activity. Exploiting light-responsive mechanisms, these ligands aim to provide a novel therapeutic modality with high spatiotemporal precision and minimal invasiveness, potentially overcoming the limitations of conventional antimicrobial agents. Starting from the discovery of an initial photoswitchable hit compound targeting LecB, we implemented a computationally guided hit-expansion strategy to identify novel photoswitchable binders with enhanced affinity in their cis-enriched form for subsequent evaluation of their antibiofilm activity. The design strategy, chemical synthesis, photochemical characterization, and preliminary biological evaluation of these compounds will be presented and discussed.