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Protein-protein interactions (PPIs) have emerged as promising targets for PPI modulators as alternative drugs because they are essential for most biochemical processes in living organisms. In recent years, a spotlight has been put on the development of peptide-based PPI inhibitors as the next-generation therapeutics to combat antimicrobial resistance taking cognizance of protein-based PPI-modulators that interact with target proteins to inhibit function. Although protein-based PPI inhibitors are not effective therapeutic agents because of their high molecular weights, they could serve as sources for peptide-based pharmaceutics if the target-inhibitor complex is accessible and well characterized. The  Escherichia coli (E. coli)  toxin protein, CbtA, has been identified as a protein-based PPI modulator that binds to the bacterial actin homolog MreB leading to the perturbation of its polymerization dynamics; and consequently has been suggested to have antibacterial properties. Unfortunately, however, the three-dimensional structures of CbtA and the MreB-CbtA complex are currently not available to facilitate the optimization process of the pharmacological properties of CbtA. In this study, computer modeling strategies were used to predict key MreB-CbtA interactions to facilitate the design of antiMreB peptide candidates. A model of the  E. coli  CbtA was built using the trRosetta software and its stability was assessed through molecular dynamics (MD) simulations. The modeling and simulations data pointed to a model with reasonable quality and stability. Also, the HADDOCK software was used to predict a possible MreB-CbtA complex, which was characterized through MD simulations and compared with MreB-MreB dimmer. The results suggest that CbtA inhibits MreB through the competitive mechanism whereby CbtA competes with MreB monomers for the interprotofilament interface leading to interference with double protofilament formation. Additionally, by using the antiBP software to predict antibacterial peptides in CbtA, and the MreB-CbtA complex as the reference structure to determine important interactions and contacts, candidate antiMreB peptides were suggested. The peptide sequences could be useful in a rational antimicrobial peptide hybridization strategy to design novel antibiotics. All-inclusive, the data reveal the molecular basis of MreB inhibition by CbtA and can be incorporated in the design/development of the next-generation antibacterial peptides targeting MreB.

Modeling the MreB-CbtA Interaction to Facilitate the Prediction and Design of Candidate Antibacterial Peptides