Numerous reports of multi-drug resistant bacterial strains have appeared in recent years, with several strains posing the threat of becoming immune against all commercially available antibiotics. It is evident that in order to prevent potential epidemic outbreaks of infectious diseases, a renewed focus on antibiotic research is highly desired, including the search for new drugs with alternative cellular targets, the investigation of the mechanisms of cytotoxicity and resistance, and the understanding of biosynthetic pathways. The threat of bioterrorism and the continuing large death toll due to infectious diseases in developing countries further underscores the need for new lines of research to combat pathogenic bacteria. Unfortunately, at this time of critical need for new antimicrobial agents, the large pharmaceutical companies have almost entirely withdrawn from this area due to small projected profits. The van der Donk group focuses on the mode of action and mechanism of biosynthesis of two classes of antibiotics that have been underexplored but have great potential for human therapeutic use, lantibiotics and phosphonate antibiotics (J. Org. Chem. 2006 71, 9561-9571.).

We are interested in the mechanism of lantibiotics for a variety of reasons. First, the enzymes that produce lantibiotics in nature are amazingly impressive catalysts. One of the enzymes studied in the laboratory breaks 14 chemical bonds and forms 10 new chemical bonds with defined stereo-, regio-, and chemoselectivity! Despite this fantastic control over chemical reactivity, we have shown that the biosynthetic enzymes are remarkably promiscuous with respect to their substrate specificity. This opens the intriguing perspective that these enzymes can be used for re-engineering the structures of naturally occurring lantibiotics to improve their properties with respect to human therapeutic use. Another reason for our interest in lantibiotics is the unusual observation that the only commercially used lantibiotic, nisin, has been used for over 40 years in more than 80 countries without widespread occurrence of bacterial resistance.

Lantibiotics are ribosomally synthesized peptide antibacterial agents. After ribosomal synthesis the peptides are modified to their bioactive forms by multi-enzyme complexes. In the first step of post-translational modification, serines and threonines are dehydrated to give dehydroalanines and dehydrobutyrines, respectively. A cyclase then catalyzes the regio- and stereoselective Michael additions of cysteine residues onto these dehydro amino acids. This provides the so called lanthionine type thioether crosslinks from which lantibiotics derive their name. In some cases one enzyme carries out both the dehydration and the cyclization steps. A typical lantibiotic contains 3-6 lanthionines in addition to several dehydroalanines (Dha) and dehydrobutyrines (Dhb). Currently more than 60 different lantibiotics have been reported.