Targeting Pseudomonas aeruginosa LecB with Photoswitchable Glycomimetic Ligands

Antimicrobial resistance (AMR) represents an escalating global health challenge, particularly in relation to nosocomial infections. A key factor driving the persistence and dissemination of AMR is the formation of biofilms, which establish a protective microenvironment that promotes microbial survival and facilitates horizontal gene transfer (1). Bacterial adhesion proteins play a fundamental role in biofilm initiation and maturation by mediating interactions between microbial cells and biotic or abiotic surfaces, ultimately enabling the development of highly resistant microbial communities. Due to their central involvement in biofilm formation, these adhesion factors have emerged as promising molecular targets for the development of alternative anti-AMR therapeutic strategies (2). Among these targets, the outer membrane virulence factor lectin LecB from Pseudomonas aeruginosa has attracted considerable interest. LecB contributes to bacterial virulence and persistence in clinical environments and exhibits strong carbohydrate-binding properties, interacting with both components of the bacterial outer membrane and exopolysaccharides within the biofilm matrix. The present work focuses on the identification and development of novel photoswitchable ligands capable of binding to and modulating LecB activity. By exploiting light-responsive control mechanisms, these compounds aim to provide a non-invasive therapeutic approach with precise spatiotemporal regulation, potentially addressing limitations associated with conventional antimicrobial treatments. Following the identification of an initial photoswitchable hit compound that established proof of concept for targeting bacterial adhesion proteins, a computationally guided hit-expansion strategy was initiated (3). This approach was designed to identify new photoswitchable LecB binders exhibiting enhanced affinity in the cis-enriched state, thereby enabling the evaluation of light-dependent antibiofilm activity. The computational studies led to the identification of several photoswitchable glycomimetics, showing higher affinity compared to the reference hitcompound, underlining the power of Computer Aided Drug Discovery (CADD) in the photopharmacology field.