Chromobacterium violaceum is a Gram-negative, rod-shaped and opportunistic human pathogen. C. violaceum is resistant to various antibiotics due to the production of quorum sensing (QS)-controlled virulence factor and biofilm formation. Hence, we need to find alternative strategies to overcome the antimicrobial resistance and biofilm formation in Gram-negative bacteria. QS is a mechanism in which bacteria's ability to regulate the virulence factors and biofilm formations leads to disease progression. Previously, hexadecanoic acid was identified as a CviR-mediated quorum-sensing inhibitor. In this study, we aimed to discover potential analogs of hexadecanoic acid as a CviR-mediated quorum-sensing inhibitor against C. violaceum by using ADME/T prediction, density functional theory, molecular docking, molecular dynamics and free energy binding calculations. ADME/T properties predicted for analogs were acceptable for human oral absorption and feasibility. The highest occupied molecular orbitals and lowest unoccupied molecular orbitals gap energies predicted and found oleic acid with -0.3748 energies. Docosatrienoic acid exhibited the highest binding affinity -8.15 Kcal/mol and strong and stable interactions with the amino acid residues on the active site of the CviR protein. These compounds on MD simulations for 100 ns show strong hydrogen-bonding interactions with the protein and remain stable inside the active site. Our results suggest hexadecanoic acid analogs could serve as anti-QS and anti-biofilm molecules for treating C. violaceum infections. However, further validation and investigation of these inhibitors against CviR are needed to claim their candidacy for clinical trials.Communicated by Ramaswamy H. Sarma.
Keywords: CviR inhibitor; Hexadecanoic acid; docosatrienoic acid; drug screening; molecular dynamics.