Antimicrobial and antibiofilm potential of α-MSH derived cationic and hydrophobic peptides against Escherichia coli: Mechanistic insight through peptide-lipopolysaccharide interactions

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The prevalence of infections caused by various Gram-negative pathogens specifically Escherichia coli continuously poses a significant challenge in health care as well as community settings owing to their ability to form biofilm and escalating tolerance towards available antibiotics. While most treatment regimes are targeted at eliminating the E. coli cells, the pathogenicity factors called endotoxin (lipopolysaccharides), associated with the sepsis initiation and the leading cause of death in intensive care units globally, are often ignored. In this study, the potency of alpha-Melanocyte Stimulating Hormone based-peptides, particularly Ana-9 and Ana-10 against E. coli was investigated through microbiological, biophysical, and microscopic assays. Both Ana-9 and Ana-10 demonstrated enhanced activity against planktonic E. coli cells, and retained their activity against biofilm, which was supported by confocal microscopy. From the mechanistic perspective, spectroscopic studies indicated that the binding of peptides with LPS led to structural alteration of peptides due to their insertion into the hydrophobic environment of LPS. The electrostatic interaction of the peptide with LPS leads to outer membrane disorganization, allowing the peptide to access the inner membrane, depolarize it and ultimately inhibit the bacterial cells within the biofilm. These observations were further confirmed by atomic force and scanning electron microscopy. Thus, this study deepens our understanding of the structural characteristics of peptides attached to LPS, which could lead to the gradual improvement in developing more potent, broad-spectrum endotoxin neutralizers.