Lasso-inspired peptides with distinct antibacterial mechanisms

Microcin J25 (MccJ25) is an antibacterial peptide with a peculiar molecular structure consisting of 21 amino acids and a unique lasso topology that makes it highly stable. We synthesized various MccJ25-derived peptides that retained some of the inhibitory activity of the native molecule against Salmonella enterica and Escherichia coli. Of the tested peptides, C1, 7-21C and WK_7-21 were the most inhibitory peptides (MIC = 1-250 µM), but all three were less potent than MccJ25. While MccJ25 was not active against Gram-positive bacteria, the three derived peptides were slightly inhibitory to Gram-positive bacteria (MIC ≥ 250 µM). At 5 µM, C1, 7-21C and WK_7-21 reduced E. coli RNA polymerase activity by respectively, 23.4, 37.4 and 65.0 %. The MccJ25 and its derived peptides all appeared to affect the respiratory apparatus of S. enterica. Based on circular dichroism and FTIR spectroscopy, the peptides also interact with bacterial membrane phospholipids. These results suggest the possibility of producing potent MccJ25-derived peptides lacking the lasso structure.