Awuni Elvis
Department of Biochemistry, School of Biological Sciences, CANS, University of Cape Coast, Cape Coast, Ghana.
Front Mol Biosci. 2022 Jan 27;8:814935. doi: 10.3389/fmolb.2021.814935. eCollection 2021.
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 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 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.
蛋白质-蛋白质相互作用（PPIs）已成为PPI调节剂作为替代药物的有前景的靶点，因为它们对活生物体中的大多数生化过程至关重要。近年来，基于肽的PPI抑制剂的开发成为焦点，作为对抗抗菌耐药性的下一代治疗方法，同时认识到基于蛋白质的PPI调节剂与靶蛋白相互作用以抑制其功能。尽管基于蛋白质的PPI抑制剂由于其高分子量而不是有效的治疗剂，但如果靶标-抑制剂复合物易于获取且特征明确，它们可以作为基于肽的药物的来源。毒素蛋白CbtA已被鉴定为一种基于蛋白质的PPI调节剂，它与细菌肌动蛋白同源物MreB结合，导致其聚合动力学受到干扰；因此，有人认为它具有抗菌特性。然而，不幸的是，目前尚无CbtA和MreB-CbtA复合物的三维结构来促进CbtA药理性质的优化过程。在本研究中，使用计算机建模策略预测关键的MreB-CbtA相互作用，以促进抗MreB肽候选物的设计。使用trRosetta软件构建了CbtA模型，并通过分子动力学（MD）模拟评估了其稳定性。建模和模拟数据表明该模型具有合理的质量和稳定性。此外，使用HADDOCK软件预测可能的MreB-CbtA复合物，通过MD模拟对其进行表征，并与MreB-MreB二聚体进行比较。结果表明，CbtA通过竞争机制抑制MreB，即CbtA与MreB单体竞争原丝间界面，导致对双原丝形成的干扰。此外，通过使用antiBP软件预测CbtA中的抗菌肽，并以MreB-CbtA复合物作为参考结构来确定重要的相互作用和接触，提出了抗MreB肽候选物。这些肽序列可用于合理的抗菌肽杂交策略以设计新型抗生素。总而言之，这些数据揭示了CbtA抑制MreB的分子基础，并可纳入针对MreB的下一代抗菌肽的设计/开发中。
