Shedding light on the key molecular determinants regulating 3D diffusion and activity of antimicrobials in bacterial biofilms.

ongoing

Bacterial biofilms are associated with approximately 1.7 million hospital-acquired infections annually in the United States, incurring an annual economic burden of about 11 billion dollars. The role of biofilms in antimicrobial resistance (AMR) is highly complex and may significantly drive resistance. Biofilms can act as a diffusion-limiting barrier against various antimicrobials resulting in limited drug access into the bacterial cells. The evaluation and quantification of biofilm diffusion is essential since it is a poorly researched topic, and the matrix properties are necessary to define the bacterial populations within the biofilm. In this project, an antimicrobial peptide (AMP) will be used as a model molecule because AMPs are known for their activity against biofilms and have been considered promising antibiofilm agents. The vCPP2319, a peptide developed by the Instituto de Medicina Molecular team (iMM), was chosen for the project as a diffusion model reporter. The research plan is organized into three scientific Work Packages (WP). WP1 aims at studying the fundamental properties of biofilms, whereas WP2 and WP3 aim at studies using vCPP2319 and the library of its variants, respectively, as molecular models to elucidate their diffusion-related properties in biofilms and correlate antibiofilm activity with the metabolic status of biofilm-embedded bacterial cells. The project will use two reference and two clinical strains of Staphylococcus aureus and Klebsiella pneumoniae as models. These bacterial species will be selected because they are clinically relevant pathogens frequently associated with biofilm infections. Overall, the project's relevance is overcoming the gap of knowledge associated with molecular diffusion in biofilms and relating the diffusion of antimicrobials within biofilms with their activity. This will enable the future development of innovative chemotherapies to fight against biofilm-related infections.