Nisin- and ripcin-derived hybrid lanthipeptides display selective antimicrobial activity against Staphylococcus aureus

Abstract

Lanthipeptides are (methyl)lanthionine ring-containing ribosomally synthesized and post-translationally modified peptides (RiPPs). Many lanthipeptides show strong antimicrobial activity against bacterial pathogens, including antibiotic-resistant bacterial pathogens. The group of disulfide bond-containing antimicrobial peptides (AMPs) is well known in nature and forms a rich source of templates for the production of novel peptides with corresponding (methyl)lanthionine analogues instead of disulfides. Here, we show that novel macrocyclic lanthipeptides (termed thanacin and ripcin) can be synthesized using the known antimicrobials thanatin and rip-thanatin as templates. Notably, the synthesized nisin(1-20)-ripcin hybrid lanthipeptides (ripcin B-G) showed selective antimicrobial activity against S. aureus, including an antibiotic-resistant MRSA strain. Interestingly, ripcin B-G, which are hybrid peptides of nisin(1-20) and ripcin, respectively, that are each inactive against Gram-negative pathogens, showed substantial antimicrobial activity against the tested Gram-negative pathogens. Moreover, ripcin B-G was highly resistant against the nisin resistance protein (NSR; a protease could cleave nisin and strongly reduce its activity), opposed to nisin itself. Mode of action studies show that ripcin C exerts its antimicrobial activity against Gram-positive pathogens by binding to the cell wall synthesis precursor lipid II and thereafter arrests cell growth. In addition, ripcin C exerts its antimicrobial activity against Gram-negative pathogens by binding to LPS and the cell wall synthesis precursor lipid II. This study provides an example of converting disulfide bond-based AMPs into (methyl)lanthionine-based macrocyclic hybrid lanthipeptides and can yield antimicrobial peptides with selective antimicrobial activity against S. aureus. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY For Table of Contents Use Only C_FIG_DISPLAY