An Engineered Nisin Analogue with a Hydrophobic Moiety Attached at Position 17 Selectively Inhibits <i>Enterococcus faecium</i> 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 <b>47</b>, featuring a benzyl group-containing tail, exhibited potent activity against various (drug-resistant) <i>E. faecium</i> strains with an MIC value (3.8 mg/L) similar to nisin, whereas its activity toward other pathogens like <i>Staphylococcus aureus</i> and <i>Bacillus cereus</i> was significantly reduced. Like nisin, the mode of action of compound <b>47</b> 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 <b>47</b> against proteolytic degradation is markedly enhanced compared to nisin. Like nisin, compound <b>47</b> was hardly hemolytic even at a very high dose. Collectively, a modified nisin variant is presented with significantly enhanced target organism specificity and stability.