Past discovery efforts have focused disproportionately on natural products that display a handful of “clinically relevant” bioactivities, e.g., antibiotics, cytotoxins, immunosuppressants, etc. Such biases constrained scientists' creativity and limited the scope of natural product discovery. We therefore direct our discovery efforts toward identifying natural products with previously overlooked bioactivities and are particularly interested in searching for ones with the ability to promote growth, regulate mutation rate, and control the persistence of microorganisms.
Our synthetic projects pursue molecular mimics, as opposed to total synthesis, of natural products that are synthetically accessible and structurally similar enough to display the same functions. For example, we drew inspiration from MccJ25 to design and synthesize conformationally restricted lasso peptides that recapitulate the function of their natural counterparts. We are also working on a combinatorial peptide library that contains the conserved DXDG motif found in members of the calcium-dependent antibiotic (CDA) family.
While humans have historically studied natural products for their "medicinally useful" bioactivities, we see natural products more broadly as part of the chemical language of living organisms. We take unconventional approaches towards natural product discovery and the study of their (bio-)syntheses.
Competition is one of many possible types of relationships between microorganisms and often manifests in the production of antibiotics. Microorganisms are also known to cooperate with each other. The production of growth promoting natural products, an activity that has largely been overlooked, is a likely manifestation of such a relationship.
A lack of diversity as a result of near-perfect replication hampers the evolution of a species. On the other hand, rapid accumulation of mutation is also detrimental. Many lines of evidence suggest that microorganisms have evolved mechanisms to tightly regulate and also actively adjust its overall mutation rate in response to the changing environment.
The persistent state (sometimes referred to as dormancy) is another evolutionary strategy to maximize the survival of a species. Mechanistic details of entering dormancy and revival are poorly understood. We believe that natural products that influence persistence can serve as powerful molecular tools to study this topic.
Conducting chemical reactions on solid-phase (resins) are advantageous in at least two ways: 1) they can be driven to near completion by adding excess reagents, and 2) resin washing serves the purpose of work-up and purification. Solid-phase synthesis has historically been used to produce linear polymers without much structural diversity. We wish to combine these advantages with the versatile synthetic tools in organic chemistry to enable the on-resin synthesis of complex bioactive small molecules.
Conserved structures in biomolecules correlate with functional importance. We first use bioinformatic tools to identify conserved sequence motifs in peptide-based natural products and then build a combinatorial library around such motifs. We envision this as a method to explore quickly and broadly chemical spaces that are close to "hot spots" of known bioactivities, which is analogous to the way organisms produce congeners of natural products.
Microcin J25 (MccJ25) is a structurally unique lasso peptide antibiotic that is effective in killing a number of drug resistant Gram-negative bacteria. Its tail threads through a loop to form a rigid 3D arrangement that has very little conformational motion. We are working on the design and production of synthetically accessible mimics that recapitulate both the structure and function of MccJ25.
Our efforts toward building a bioinformatic algorithm to predict the final structure of nonribosomal peptides (NRP) entails two parts. We are 1) developing an assay to quickly identify the amino acid substrate of adenylation domains, and 2) studying the mechanistic details of thioesterase catalyzed NRP cyclization.