Evaluating the MreB-Binding Prospects of Proposed Antibacterial Peptides through Molecular Modeling and Simulations

Bacterial infection and resistance continue to pose a threat to global health. Antibacterial peptides have been proposed as next-generation therapeutics to address this threat owing to their reduced susceptibility to resistance. The interprotofilament interface of the bacterial actin MreB is a prospective target for peptide-based antibiotics to impede MreB polymerization into the double protofilaments required for function. Unfortunately, there have been no reports of inhibitors of MreB targeting the interprotofilament interface. In this study, molecular modeling and simulation strategies were used to assess the MreB-binding prospects of four proposed antiMreB peptides to identify leads for the design and development of peptide-based antibiotics. The PEP-FOLD server was employed to predict the structures of the peptides, followed by structural refinement using the ModRifner server. Subsequently, the HADDOCK server was used to predict the mode of binding of each peptide to the interprotofilament interface of MreB. Furthermore, the predicted peptide-MreB complexes were subjected to molecular dynamics simulations, identifying Pep4 and Pep7 as hits. The results showed that Pep4 and Pep7 remained stably bound to the interprotofilament interface of MreB for up to 100 ns of simulation time. In addition to demonstrating the possibility of binding to the interprotofilament interface of MreB to disrupt MreB–MreB interactions, Pep4 and Pep7 also showed the ability to impede the ATP-dependent conformational change and dynamics of MreB required for polymerization into double protofilaments. Collectively, the results suggest that Pep4 and Pep7 are potential inhibitors or leads for the design, discovery and development of peptide-based MreB-targeting antibiotics.