Lantibiotics and Similar Peptides Produced by and Active on Gram-Positives: Discovery, Development and Perspectives

Abstract

Lantibiotics are a group of ribosomally synthesised peptides that contain post-translational modifications consisting of (methyl)lanthionine residues forming bridges that confer them characteristic structures. Most lantibiotics are antibacterials that bind to the cell wall precursor lipid II. They can be rod shaped or globular depending on the distribution of the lanthionine residues. Their biosynthetic pathway is relatively simple when compared to other secondary metabolites. Due to this simplicity, genetic manipulation of the pathways is a very attractive tool to obtain variants that might have improved properties. Mutagenesis programmes have shown that the biosynthetic machinery of lantibiotics has relaxed specificity allowing the production of large collections of variants. Lantibiotic gene clusters are a common feature within bacteria, particularly Gram-positive organisms. Genome mining and in vitro synthesis experiments suggest that there is a great potential for discovery of new lantibiotics. With the increasing need for effective antibiotics against multidrug-resistant pathogens, lantibiotics are an attractive option for a new class of molecules. There are two lantibiotics in late preclinical development for use against systemic Gram-positive infections, one lantibiotic in Phase 1 clinical trials for the treatment of Clostridium difficile infections and another lantibiotic in Phase 2b for the treatment of cystic fibrosis. The potential of lantibiotics for the treatment of bacterial infections should become a reality in the next few years with the current compounds going through the corresponding drug development stages and new compounds joining the collection of useful compounds in the fight against multidrug-resistant bacteria.