Binding of cationic analogues of α-MSH to lipopolysaccharide and disruption of the cytoplasmic membranes caused bactericidal action against Escherichia coli

In earlier reports, we have shown the antimicrobial activity of a host neuropeptide, alpha-melanocyte stimulating hormone (alpha-MSH) and its cationic analogues against Staphylococcus aureus. These analogues of alpha-MSH showed enhanced staphylocidal activity without any significant mammalian cell toxicity. Therefore, here, we explored the antimicrobial activity of alpha-MSH and its cationic analogues against Escherichia coli. Though the presence of lipopolysaccharide (LPS) in Gram-negative bacteria enables them to resist most conventional antibiotics, encouragingly alpha-MSH and its four analogues showed killing of both logarithmic and stationary phase E. coli cells in a time, dose and cationicity-dependent manner. In fact, the most cationic analogue, KKK-MSH with a + 5 charge, demonstrated successful eradication of 10(5) CFU/mL of E. coli cells within 15 min at a concentration as low as 1 mu M. BC displacement experiment revealed that cationicity of the peptides was directly related to the killing efficacy of these alpha-MSH analogues against E. coli cells via initial LPS-binding, leading to rapid disruption of the LPS-outer membrane complex followed by inner bacterial membrane damage and eventual cell death. Here, we propose alpha-MSH based cationic peptides as promising future agents with broad-spectrum antibacterial efficacy against both Gram-negative and Gram-positive pathogens.

Automated summary

In this study, the antimicrobial activity of alpha-MSH and its cationic analogues against Escherichia coli was investigated. The results showed that these analogues demonstrated killing of both logarithmic and stationary phase E. coli cells in a time, dose and cationicity-dependent manner. The most cationic analogue, KKK-MSH, successfully eradicated E. coli cells within 15 minutes at a concentration as low as 1 μM. The study suggests that alpha-MSH based cationic peptides hold promise as future agents with broad-spectrum antibacterial efficacy against both Gram-negative and Gram-positive pathogens.