Spatiotemporal Control of Bacterial Adhesion via Light-Responsive Modulators

Antimicrobial resistance (AMR) poses a growing global health threat, particularly in the context of hospital-acquired infections. One of the major contributors to the persistence and spread of AMR is biofilm formation, which creates a protective microenvironment that enhances microbial survival and facilitates horizontal gene transfer [1]. Central to biofilm development are bacterial adhesion proteins, which mediate crucial interactions between microbial cells and surfaces, thereby supporting the proliferation of highly resistant microbial communities. Owing to their pivotal role in biofilm formation, adhesion proteins have emerged as attractive targets for the development of novel anti-AMR strategies [2,3]. Among these targets, the virulence factor LecB-lectin, located on the outer membrane of Pseudomonas aeruginosa, has received particular attention. LecB not only contributes significantly to the pathogen’s virulence and persistence in clinical settings, but also demonstrates strong carbohydrate-binding activity, interacting with both the bacterial outer membrane and exopolysaccharides within the biofilm matrix. This project aims to identify and develop innovative photoswitchable ligands capable of binding and modulating LecB activity. Utilizing light-responsive mechanisms, these ligands are designed to offer a novel therapeutic approach with high spatiotemporal control and minimal invasiveness, potentially overcoming limitations associated with traditional antimicrobial treatments. Beginning with the identification of an initial photoswitchable hit compound, which provides proof of concept for this therapeutic strategy targeting bacterial adhesion proteins, right after we started a computationally guided hit expansion program. This approach sought to discover new photoswitchable binders with enhanced affinity in the cis-enriched form for evaluating light-dependent antibiofilm properties of the compounds. The design rationale, synthetic pathways, photochemical characterization, and preliminary biological assessment of these compounds will be presented and discussed.