Research Overview

Microorganisms are capable of synthesizing structurally complex and medicinally relevant polyketides in “one-pot” aqueous reactions.

Many of these polyketides contain moieties that impart important pharmaceutically relevant properties but represent a significant challenge to build via traditional synthetic organic approaches. This phenomenon has inspired chemists and biologists to understand how nature controls these syntheses and how humans can harness biological systems to better human health and the environment. Our research focuses on the elucidation of bacterial biosynthetic mechanisms with the concomitant goals of developing environmentally responsible chemical tools for general organic syntheses and making novel therapeutic agents.

We currently are asking the following questions:

1) How do bacteria make aryl-aryl bonds?

We seek to answer this question by conducting a bioinformatics analysis of the genomes of microorganisms that product secondary metabolites with this structural motif and biochemically characterizing candidate enzymes. The fundamental scientific knowledge gained from this pilot study will not only enable the development of new biocatalysts for organic synthesis, but also can be applied in manufacturing new antibiotics and used as input for refined genome mining studies. Compared to chemical-based methods, a biocatalytic approach to coupling two aryl molecules offers the potential for better atom/step economy as well as a vastly improved environmental profile through reduced solvent, reagent, and consumable usage.

Investigators: Emily Wineset and Noah Bloch
2) How did polyketide synthases evolve and what does this mean for the discovery of new molecules and biocatalysts?

In collaboration with Dr. Maureen Hillenmeyer at Stanford University, we are exploring the evolution of the enzyme assemblies that organisms use to make structually diverse and complex molecules. Using the tools of computational biology, we can identify important trends and predict which gene clusters and genes that show partricular promise for bioprospecting. We then turn to molecular biology and bioorganic chemistry to characterize the enzymes and small molecules encoded by the candidate genes.

Investigator: Erin Berlew; Collaborator: Dr. Maureen Hillenmeyer
3) Can we use precursor-directed biosynthesis to make new vancomycin-like drugs?

Complestatin, a member of the vancomycin group of natural products, is produced by Streptomyces lavendulae and has a remarkable track record as a modulator of a variety of pharmaceutically interesting protein-protein interactions. While it is an attractive target for analoging, the structural complexity of the natural product has limited the production of analogs through traditional synthetic routes. The goal of this research project is to harness the complestatin biosynthetic machinery such that analoging can be achieved through a combination of synthesis and biosynthesis. In particular, we are interested in understanding the mechanism of aryl-aryl and aryl-ether-aryl bond formation.

Investigators: Niki von Krusensteirn and Josh Bulos
4) Can we use vibrational spectroscopy to learn about the fundamental mechanisms by which bacteria make antibiotics?

Acyl carrier proteins (ACPs) are considered the workhorse of the polyketide synthase (PKS) machineries responsible for producing antibiotics in microorganisms. These enzymes are capable of protecting reactive intermediates while mediating numerous reactions and protein-protein interactions, all of which contribute to the efficiency of PKSs. We seek to understand the molecular basis for this remarkable feat by studying ACP conformational dynamics. In collaboration with Casey Londergan, we have shown that we can convert the terminal thiol of any ACP's phosphopantetheine arm to a thiocynate vibrational spectroscopic probe capable of reporting on local solvation states. In doing so, we have installed a "helmet camera" on the reactive site of a very important protein!

Investigators: Connie Friedman and Michael Jordan; Collaborator: Casey Londergan
5) Can we use Streptomyces bacteria as a platform to introduce underrepresented elementary students in the local community to the sciences?

In addition to exploring the role of Streptomyces secondary metabolites as therapeutic agents, we are also interested in leveraging the beauty of pigment-producing organisms to create living art. We enjoy playing in the fertile ground between art and science by using our bacterial strains to produce living images as well as biopaint. We now seek to develop an outreach program to encourage underrepresented elementary school students to explore chemistry through by creating bioart.