Functional and Toxicological Evaluation of MAA-41: A Novel Rationally Designed Antimicrobial Peptide Using Hybridization and Modification Methods from LL-37 and BMAP-28

Background: Managing bacterial infections caused by multidrug-resistant (MDR) and biofilmforming bacteria is a global health concern. Therefore, enormous efforts were directed toward finding potential alternative antimicrobial agents, such as antimicrobial peptides (AMPs). Aim: We aimed to synthesize a novel modified hybrid peptide designed from natural parents’ peptides with enhanced activity and reduced toxicity profile. Methods: Rational design was used to hybridize the two antimicrobial peptides, in which the alpha-helical parts of BMAP-28 and LL-37 were combined. Then, several amino acid modifications were applied to generate a modified hybrid peptide named MAA-41. The physicochemical properties were checked using in silico methods. The MAA-41 was evaluated for its antimicrobial and anti-biofilm activities. Synergistic studies were performed with five conventional antibiotics. Finally, the cytotoxicity on mammalian cells and the hemolytic activity were assessed. Results: The MAA-41 revealed a broad-spectrum activity against Gram-positive and Gram-negative bacteria, including standard and MDR bacterial strains. The concentration against planktonic cells ranged between 10 and 20 μM, with higher potency against Gram-negative bacteria. The MAA-41 displayed potent activity in eradicating biofilm-forming cells, and the MBECs were equal to the MIC values reported for planktonic cells. This new peptide exhibited reduced toxicity profiles against erythrocyte cells but not against Vero cells. Combining MAA-41 peptides with conventional antibiotics improved the antimicrobial activity of the combined agents. Either synergistic or additive effects were shown as a significant decrease in MIC to 0.25 μM. Conclusion: This study proposes the validity of a novel peptide (MAA-41) with enhanced antimicrobial activity and reduced toxicity, especially when used as conventional antibiotic combinations.