title: Perspectives on lantibiotic discovery - where have we failed and what improvements are required?
abstract: The increasing resistance of bacteria to conventional antimicrobial therapy within both the nosocomial and community environment has enforced the urgent requirement for the discovery of novel agents. This has stimulated increased research efforts within the field of lantibiotic discovery. Lantibiotics are ribosomally synthesised, post-translationally modified antimicrobial peptides that exhibit antimicrobial activity against a range of multi-drug-resistant (MDR) bacteria. The success of these agents as a novel treatment of MDR infections is exemplified by: the clinical development of MU1140 (mutacin 1140) and NAI-107 (microbisporicin), which are in late pre-clinical trials against gram-positive bacteria; NVB302 that has completed Phase I clinical trials for the treatment of Clostridium difficile infections and; duramycin that has completed Phase II clinical trials in the treatment of cystic fibrosis. Despite these potential successes, the traditional method of lantibiotic discovery involving the induction, production and identification is often an inefficient, time-consuming process creating a barrier to the efficient discovery of novel lantibiotics. The introduction of novel and innovative identification methods, including the application of probes and the ability to improve the stability and activity of agents via mutagenesis offer encouraging new areas to explore. The rapid expansion of available genome sequences of a wide variety of bacteria has revealed multiple interesting lantibiotic clusters that have the potential to be effective antimicrobials. However, due to the inefficient expression, screening and production methods currently employed, they are being assessed inefficiently and not rapidly enough to keep up with the ever-increasing demand for new agents.
authors.affiliation: Institute of Pharmaceutical Sciences, King's College London , Britannia House, 7 Trinity Street, SE1 1DB London , UK Stephanie.sandiford@kcl.ac.uk.
authors.forename: Stephanie Kate
authors.initials: SK
authors.lastname: Sandiford
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001430:Bacteriocins / Q000494:pharmacology*; D015195:Drug Design; D055808:Drug Discovery; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins
keywords: anti-microbial; biosynthesis; genome mining; heterologous expression; infectious disease; microbial resistance