Design of novel anti-quorum sensing peptides targeting LuxO to combat Vibrio cholerae pathogenesis.

Vibrio cholerae, the Gram-negative bacterium abruptly colonizes the human intestine causing diarrhea, employing quorum sensing (QS) system as the major survival technique for mediating biofilm formation, virulence, competence, etc. Two distinct QS systems coordinated by the auto-inducer molecules, cholera-specific CqsA/S system and universal LuxS/PQ system, operate in parallel converging into a common phosphorelay pathway involving LuxU and LuxO. The master regulatory proteins of the QS system, AphA and HapR regulate the biofilm formation based on cell density, whose expression is controlled by the global response regulator LuxO. At low cell density, activated LuxO indirectly represses HapR, favoring the virulence cascade expression. Rather at high cell densities, LuxO represses AphA expression subsequently blocking the expression of virulence factors. Hence, targeting LuxO would be a promising strategy to downregulate the virulence pathway and modulate the QS system. With this insight, the present study has been designed to intrude the interaction between LuxU and LuxO through in silico design of novel peptides and validation of these peptides through molecular simulations. QS peptides were designed using QSPred server by altering the template sequence representing the LuxU-LuxO interaction, among which PEP8 exhibited better interaction and stability with the target protein LuxO. These in silico designed novel peptides would serve as potential target-specific molecules that would inhibit the LuxU-LuxO interaction and modulate the QS system to restrict Vibrio cholerae pathogenesis. However, further in vitro validations would substantiate the efficacy of these novel QS peptides. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-023-00172-2.