Molecular Dynamics and Docking Simulations in Exploring a Potential Extracellular Matrix-Based Antibiofilm: Fighting the Resistant Pseudomonas aeruginosa-Candida albicans

Glycosyltransferase activity of Bgl2 which mediates 1,3 beta-glucan biosynthesis, and phosphomannomutase/phosphoglucomutase (PMM/PGM) which catalyzes the synthesis of precursors for alginate and the O-antigen chain of lipopolysaccharide, are key enzymes in C. albicans and P. aeruginosa, respectively. These enzymes facilitate the synthesis of extracellular matrix components in biofilms. This study aimed to identify potential ligands in silico that demonstrate conformational fitness with the active sites of both Bgl2 and PMM/PGM, and to experimentally determine their inhibitory effects on the extracellular matrix formation in C. albicans-P. aeruginosa mix biofilms. Additionally, the study evaluated the effects of these ligands in combinatorial antibiofilm treatments with fluconazole and meropenem. Molecular docking and molecular dynamics (MD) simulations predicted glucosamine to act as a competitive inhibitor of both Bgl2 and PMM/PGM. The dynamic behavior of glucosamine indicated stable binding within the active site pockets of these target proteins. In vitro experiments demonstrated that glucosamine inhibited the formation of the extracellular matrix in C. albicans, P. aeruginosa, and C. albicans-P. aeruginosa biofilms by 76.5%, 51.0%, and 45.1%, respectively. Furthermore, glucosamine enhanced the efficacy of fluconazole and meropenem against C. albicans-P. aeruginosa biofilms. The combination of fluconazole (8-fold MIC) and meropenem (1-fold MIC) resulted in the highest and complete suppression.