BamA Targeted Design of Antimicrobial Peptides with High Efficacy and Low Toxicity

The emerging of superbugs has led to an urgent need for novel antibiotics. Antimicrobial peptides (AMPs) characterized with broad-spectrum antibacterial activity, reduced resistance, and immune stimulation, show application prospects in combating drug-resistant microorganisms. In this study, computational techniques were used to design BamA targeted AMPs. Designed AMPs were then synthesized and investigated for their antibacterial activities, mechanisms, and stability. Molecular docking and dynamics simulations revealed that both the designed AMPs of 11pep and D-11pep could polymerize the β1, β9, β15, and β16 chains of BamA, leading to faulty folding of outer membrane proteins and resulting in antibacterial effects. Further antibacterial studies showed that 11pep and D-11pep have broad-spectrum activity, and D-11pep exhibiting more potent antibacterial action against resistant Gram-negative bacteria with MICs of 16 μg/mL, 8 μg/mL and 32 μg/mL against carbapenem-resistant Escherichia coli, carbapenem-resistant Pseudomonas aeruginosa, and multi-drug resistant Acinetobacter baumannii, respectively, and lower resistance induction. Mechanism investigation of 11pep and D-11pep showed that, both peptides could disrupt the bacterial outer membrane, which was consistent with the molecular dynamics simulations, and D-11pep is more stable and less toxic than 11pep. Results in this study indicate that rational design of AMPs targeted BamA, and the D-amino acid replacement strategy are useful tactics to develop drug-resistant bacteria AMPs.