Development of a class II lanthipeptide production system

Drug resistance of bacterial pathogens has become a serious problem in healthcare. To overcome resistance, a new generation of antimicrobial compounds based on novel structures is needed. Lanthipeptides are small ribosomally produced peptides that contain so-called lanthionine rings. These peptides often are equipped with antimicrobial activity and are then termed lantibiotics. These lantibiotics may form an alternative to classical antibiotics. This thesis focuses on the development of a generic production system for lanthipeptides. The envisioned production system contains a known lantibiotic modification enzyme and possibly the associated transporter for secretion into the external medium. With the Gram-positive bacterium Lactococcus lactis as a production host, production of a bioactive lantibiotic was realized when expressed together with its cognate modification enzyme and transporter. However, the system turned out to be too specific for its natural lanthipeptide giving poor yields of unrelated lanthipeptides. Therefore, Escherichia coli was used as an alternative host but now for intracellular production skipping the transport step. With this system several lanthipeptides could be produced that underwent the expected modifications. Therefore, E. coli appears a good host for lanthipeptide production with the potential to be developed into a generic system