Modulation of bacterial cell adhesion proteins via photoswitchable ligand: a promising strategy to counteract biofilm formation

Antimicrobial resistance (AMR) is an escalating global threat, posing a critical challenge to modern medicine, particularly in the context of nosocomial infections. Among the various factors driving the spread of AMR, biofilm formation represents a major contributor, as it provides a protective niche for pathogens and facilitates the horizontal transfer of resistance genes across species [1]. Central to biofilm formation are bacterial cell adhesion proteins, which mediate cell-to-cell and cell-to-surface interactions, enabling the development of dense microbial communities that exhibit heightened resistance to antimicrobial agents. Given their pivotal role in biofilm formation, adhesion proteins represent ever-increasing attractive therapeutic targets for the treatment of AMR. Among the different potential adhesion proteins target, bacteria Virulence Factor (LecB) protein, a bacterial outer- membrane protein of Pseudomonas aeruginosa (a notable gram-negative pathogen causing hospital- acquired infections), aroused interest both for the major threat of this strain to current and future healthcare worldwide and for its ability to bind carbohydrate moieties in the P. aeruginosa outer membrane as well as exopolysaccharides in the biofilm matrix [2,3]. Considering what mentioned before, this project aims at identifying and developing novel photoswitchable ligands capable of binding to and modulating the activity of LecB protein for the treatment of AMR. By leveraging light-activated protocols, these ligands could offer a promising alternative to conventional antimicrobials, providing a non-invasive approach with precise spatial and temporal control. The design strategy, the chemical synthesis and the proper photochemical characterization as well as the preliminary biological evaluation will be presented and discussed. References [1] Kauser, A., Parisini, E., Suarato, G., & Castagna, R. (2023). Light-Based Anti-Biofilm and antibacterial strategies. Pharmaceutics, 15(8),2106. https://doi.org/10.3390/pharmaceutics15082106 [2] Thuenauer, R., Landi, A., Trefzer, A., Altmann, S., Wehrum, S., Eierhoff, T., Diedrich, B., Dengjel, J., Nyström, A., Imberty, A., & Römer, W. (2020). The Pseudomonas aeruginosa Lectin LecB Causes Integrin Internalization and Inhibits Epithelial Wound Healing. MBio, 11(2). https://doi.org/10.1128/mbio.03260-19 [3] Sommer, R., Hauck, D., Varrot, A., Wagner, S., Audfray, A., Prestel, A., Möller, H. M., Imberty, A., & Titz, A. (2015). Cinnamide Derivatives of D-Mannose as Inhibitors of the Bacterial Virulence Factor LecB from Pseudomonas aeruginosa. ChemistryOpen, 4(6), 756–767. https://doi.org/10.1002/open.201500162