Our research program focuses on the discovery and design of new antibiotics and natural products. These projects combine synthetic organic and protein chemistry to address problems at the interface of chemistry and biology.

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. 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at this time of critical need for new antimicrobial agents, the large pharmaceutical companies have almost entirely withdrawn from this area due to small projected profits.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.

Cyclic peptides are attracting increased attention for their potential applications. They are metabolically more stable than linear peptides and are promising candidates for disruption of protein-protein interactions. Natural product cyclic peptides are generated by both non-ribosomal and ribosomal pathways. The molecules produced by the latter route have rapidly expanded in recent years as a consequence of the explosion in genomic sequence information. These pathways, in which a linear precursor peptide is generated ribosomally and subsequently post-translationally modified, provide many attractive opportunities for bioengineering. First, the amino acid sequence is genetically encoded, allowing site-directed mutagenesis approaches to access analogues. Second, the pathways towards these compounds usually involve a relatively small number of biosynthetic enzymes. In turn, such relatively short pathways are more amenable to bioengineering approaches. Third, the biosynthetic enzymes are often highly promiscuous. We have demonstrated that genome mining can uncover new cyclic peptides with novel structures and activities and we have shown that these pathways lend themselves well for engineering.

Natural products containing carbon-phosphorus bonds (phosphonic and phosphinic acids) have found widespread use in medicine and agriculture. Recent years have seen a renewed interest in the biochemistry and biology of these compounds with the cloning of the biosynthetic gene clusters for several family members. With the Metcalf group in Microbioloyg, the Nair group in Biochemistry, and the Zhao group in Chemical and Biomolecular Engineering, our group has developed discovery methods for novel phosphonate natural products and has investigated the unprecedented chemistry that takes place during their biosyntheses.

In summary, we use genome mining strategies to discover new natural products, use microbiology and genomic tools to determine their mode of action, use chemical biology techniques to study their biosynthesis, and use synthetic chemistry to improve their activities and therapeutic properties.