Interaction with lipopolysaccharide is key to efficacy of tryptophan- and arginine-rich α-melanocyte-stimulating hormone analogs against Gram-negative bacteria.

In order to search for novel antibacterial therapeutics against Gram-negative bacteria, the antibacterial efficacies and mechanism of action of tryptophan- and arginine-rich α-melanocyte-stimulating hormone analogs were investigated. We performed a killing assay to determine their efficacy; fluorescence, microscopic studies were used to understand their mechanism and peptide-lipopolysaccharide interaction. A checkerboard assay was used to find the effective combination of peptide and antibiotics. Ana-peptides displayed good killing activity against , and . Their strong interaction with lipopolysaccharide damaged the bacterial membranes and led to their subsequent death. Ana-5, the highest cationic and hydrophobic analog, emerged as the most potent peptide, showing synergistic action with rifampicin and erythromycin. Ana-5 can be presented as an important therapeutic candidate against bacterial infections.