Light-Responsive Modulators of Bacterial Cell Adhesion Proteins: a Novel Strategy against AMR?

Antimicrobial resistance (AMR) represents an increasingly serious global health concern, particularly within the context of hospital-acquired infections. A key factor contributing to the persistence and dissemination of AMR is the formation of biofilms, which provide a protective microenvironment that enhances microbial survival and facilitates horizontal gene transfer[1]. Central to the proliferation of biofilms are bacterial adhesion proteins, which mediate critical interactions between microbial cells and surfaces, thereby supporting the development of highly resistant microbial communities. Due to their essential role in biofilm formation, adhesion proteins have emerged as promising targets for novel anti-AMR strategies. [2,3]. Among these adhesion proteins, the virulence factor LecB, a lectin located on the outer membrane of Pseudomonas aeruginosa, not only contributes to the high virulence and persistence of pathogens in healthcare settings but also exhibits strong carbohydrate-binding properties, interacting with both the bacterial outer membrane and exopolysaccharides within the biofilm matrix. Therefore, LecB has become increasingly popular as a putative antibiofilm druggable target. This research project focuses on the identification and development of innovative photoswitchable ligands designed to bind and modulate LecB activity. By means of light-responsive mechanisms, these ligands should provide a novel therapeutic modality characterized by spatiotemporal precision and minimal invasiveness, thus potentially circumventing the limitations of conventional antimicrobial agents. Starting from the identification of the first photoswitchable hit compound targeting this bacterial cell adhesion protein, we performed a computationally guided hit expansion program to identify novel photoswitchable binders with improved affinity in the cis-enriched form to be tested for their antibiofilm properties. The design strategy, the chemical synthesis and photochemical characterization as well as the preliminary biological evaluation will be presented and discussed.