Kar, A.; Borah, A.; Malik, V.; Srivastava, A.; Mandal, K.

Combatting biofilm-associated methicillin-resistant Staphylococcus aureus (MRSA) infections remains a formidable challenge, largely due to bacteria's heightened resistance to antibiotics and evasion of the host's immune responses. Inhibiting biofilm formation or promoting biofilm dissolution is believed to disrupt the protective matrices and expose bacterial cells to immune clearance or antimicrobial treatments. Cross- helical amyloid fibrils of phenol-soluble modulins are the key structural components of the MRSA biofilm. In this study, we present a novel retro-inverso peptide that successfully inhibits cross- amyloid formation, induces disassembly of pre-formed fibrils of the biofilm-forming modulin peptide, and efficiently disperses MRSA biofilm biomass in a dose-dependent manner. The biophysical studies of the interaction of the designed peptide and modulins have suggested a mechanism for the biofilm disruption. The findings highlight the potential of the proteolytically resistant mirror-image peptide as a promising therapeutic agent for the treatment of biofilm-associated MRSA infections.