Engineering of Nisin as a Means for Improvement of Its Pharmacological Properties: A Review

Abstract

Lantibiotics are believed to have a conceivable potential to be used as therapeutics, especially against clinically resistant bacterial strains. However, their low solubility and poor stability under physiological conditions limit their availability for clinical studies and further pharmaceutical commercialization. Nisin is a readily available and cheap lanthipeptide and thus serves as a good model in the search for the tools to engineer lantibiotics with improved pharmacological properties. This review aims to address technologies that can be applied to alter and enhance the antimicrobial activity, antibacterial spectrum and physicochemical properties (solubility, solution stability and protease resistance) of nisin. There are basically two general means to obtain nisin analogs—protein engineering and chemical functionalization of this antibiotic. Although bioengineering techniques have been well developed and enable the creation of nisin mutants of variable structures and properties, they are lacking spectacular effects so far. Chemical modifications of nisin based on utilization of the reactivity of its free amino and carboxylic moieties, as well as reactivity of the double bonds of its dehydroamino acids, are in their infancy.

Nisin-based therapy: a realistic and eco-friendly biocontrol strategy to contrast Xylella fastidiosa subsp. pauca infections in planta

“…Most importantly, FM and TEM results showed that nisin promptly reacts with Xf within the first 15 min of contact, leading to an immediate and complete lysis of the cellular membrane and with high potency. This observed effect aligns with the well-documented attributes of nisin, characterized by cationic and hydrophobic peptides ( Musiejuk and Kafarski, 2023 ). The rapid and robust impact of nisin on Xf cells over a brief timeframe is most probably due to the high binding affinity of nisin to lipid II, disrupting the lipid bilayer.…”

Rombocin, a Short Stable Natural Nisin Variant, Displays Selective Antimicrobial Activity against Listeria monocytogenes and Employs a Dual Mode of Action to Kill Target Bacterial Strains

“…This broad substrate specificity of the nisin dehydrating and transport machinery suggests that lantibiotic enzymes could be utilized for the synthesis of a wide range of novel dehydroresidue-containing peptides or novel lantibiotic structures. Building upon these advantages, nisin has been bioengineered to enhance its antimicrobial activity, heat stability, solubility, diffusion, and protease sensitivity. , In this study, we further expand the utility of nisin-controlled expression systems and NisBTC modification machinery, which uses a method for inducing modification enzymes in advance to enhance the peptide modification efficiency (Figure ). The development of an efficient heterologous modification system offers significant advantages, facilitating the characterization and further modification of novel lantibiotics.…”

“…Lantibiotics are gene-encoded, a feature that makes them amenable to bioengineering. Mutagenesis of lantibiotics has been widely performed to improve their antimicrobial and physicochemical properties . Nisin Z is cationic due to the presence of four positively charged residues (K12, K22, K34, and H31) and the absence of negatively charged equivalents.…”

“…Mutagenesis of lantibiotics has been widely performed to improve their antimicrobial and physicochemical properties. 25 Nisin Z is cationic due to the presence of four positively charged residues (K12, K22, K34, and H31) and the absence of negatively charged equivalents. The importance of positive charge is given to the initial attraction of many cationic peptides to the cell envelope.…”

Nisin—A Promising Antimicrobial Compound from Lactic Acid Bacteria

“…If the pyrophosphate portion of lipid II is removed, the affinity of nisin for lipid II decreases dramatically [9]. After the N-terminal sequence binds to the cell wall and forms a cage-like structure, the C-terminal sequence of nisin flips over into the bacterial cell membrane [10]. In this process, the hinge-like region that connects the two structural domains also plays an important role.…”