Antibiotic development has passed its peak, yet new antibiotics have never been more necessary in relation to the rising antibiotic resistance rate. The high prevalence of multidrug resistance (MDR) bacterial infections, due to microbes’ ability to overcome antibiotics, is a huge burden to the healthcare system. The aim of this study was to design a novel altered hybrid peptide named HEA-9 from the natural parent peptides BAMP-27 and cecropin A with improved activity and selectivity. HEA-9 was rationally designed by hybridizing the active residues of the parent peptides. This was followed by an amino acid modification to enhance the physicochemical properties of HEA-9, which were evaluated using in silico tools. Thereafter, the in vitro antibacterial activities of HEA-9 against sensitive and MDR strains of Gram-negative and Gram-positive bacteria were measured. Furthermore, the antibiofilm activities against MDR bacteria were evaluated. Moreover, synergistic experiments with four conventional antibiotics were conducted against all tested bacteria. Finally, we used Vero cells to assess HEA-9/associated cytotoxicity incorporated into mammalian cells, and we examined its hemolytic activity on erythrocytes. HEA-9 expressed extensive activity against sensitive and MDR strains of Staphylococcus aureus and Escherichia coli bacteria, having a 12.5 μM minimum inhibitory concentration (MIC)/MBC. HEA-9 was also capable of eradicating biofilms, with reported minimal biofilm eradication concentrations of 100 and 25 μM for MDR E. coli and MDR S. aureus, respectively. Also, HEA-9 demonstrated superior toxicity profiles against erythrocyte cells and Vero cells. Combinations of HEA-9 with conventional antibiotics resulted in a considerable enhancement in the antibacterial activity of the combined drugs. Interestingly, the MIC of HEA-9 in conjunction with traditional antibiotics decreased up to 0.098 μM in certain situations. In conclusion, the HEA-9 peptide has shown improved activity and selectivity either alone or in combination with conventional antibiotics, making it a promising candidate for treating MDR bacterial infections.
Key words: Antimicrobial peptides, rational design, hybridization, antimicrobial resistance, MDR bacteria, antibiofilm activity, synergism
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