An Engineered Nisin Analogue with a Hydrophobic Moiety Attached at Position 17 Selectively Inhibits Strains.

Antibiotic resistance is one of the most challenging global public health concerns. It results from the misuse and overuse of broad-spectrum antibiotics, which enhance the dissemination of resistance across diverse bacterial species. Antibiotics like nisin and teixobactin do not target an essential protein and employ a dual mode of action antibacterial mechanism, thereby being less prone to induce resistance. There is a need for the development of a potent narrow-spectrum dual-mode-acting antibiotic against human pathogens. Using nisin, a lantibiotic with potent antimicrobial activity against many pathogens, as a template, the unnatural amino acid azidohomoalanine was introduced at selected positions and subsequently modified using click chemistry with 14 alkyne-moiety containing tails. A novel nisin variant, compound , featuring a benzyl group-containing tail, exhibited potent activity against various (drug-resistant) strains with an MIC value (3.8 mg/L) similar to nisin, whereas its activity toward other pathogens like and was significantly reduced. Like nisin, the mode of action of compound results from the inhibition of cell wall synthesis by binding to lipid II and nisin-lipid II hybrid-pore formation in the outer membrane. The resistance of compound against proteolytic degradation is markedly enhanced compared to nisin. Like nisin, compound was hardly hemolytic even at a very high dose. Collectively, a modified nisin variant is presented with significantly enhanced target organism specificity and stability.