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How do living organisms like bacteria and lower fungi produce and respond to biologically active small molecules?

We are interested in how living organisms, especially bacteria and lower fungi, produce and respond to biologically active small molecules. These molecules include natural products known as ‘specialized metabolites’ as well as synthetic compounds identified in small molecule libraries.

The questions we’re interested in include the role played by these chemical responses in nature and developing chemical probes to understand new biology and for development as antibiotics.

All organisms communicate and compete using chemistry. Bacteria produce well-known molecules that inhibit the growth of competing organisms: many of these have been developed as antibiotics.

The most important producers of specialized metabolites are streptomycetes: their products include front line antibiotics such as vancomycin, streptomycin, erythromycin, and numerous others. The sequencing of bacterial genomes, revealed that the diversity of these molecules is much greater than previously appreciated. It turns out however, that many of the specialized metabolites genes are not expressed during laboratory growth.

One of our interests is to find ways to activate these genes, identify, purify and study the compounds they produce.

The long-term goal is a full understanding of all biologically active molecules on earth.

WAC extract collection
A colorful WAC extract collection grown in Nodwell Lab.

The majority of the known antibiotics target RNA polymerase, DNA gyrase, the ribosome, the biosynthesis of nucleotides and the biosynthesis of the cell wall. Are there ways to identify inhibitors of other targets that could serve as a basis for antibiotic discovery?

Streptomyces coelicolor, the model actinomycete, produces a diffusible blue pigment with antibiotic activity called actinorhodin.
Streptomyces coelicolor, the model actinomycete, produces a diffusible blue pigment with antibiotic activity called actinorhodin.

Our approach has been to identify molecules that block sporulation, but not vegetative growth, in the filamentous bacterium Streptomyces coelicolor. This remarkable bacterium employs the molecular apparatus for cell division, chromosome segregation and other molecular pathways in different ways than other bacteria. As a result, the inhibition of some important molecular targets results in a sporulation block that can be easily identified and studied. Through this work we have identified novel synthetic molecules that block critical processes such as cell division, the electrochemical gradient across the cell membrane and a mechanism that controls cell size.

A fascinating thing that has become clear as we have identified new natural products is that these molecules can target eukaryotes as well as prokaryotes. Indeed, some well-known anti-cancer (doxorubicin) and immune suppressants (rapamycin) are specialized metabolites produced by streptomyetes bacteria.

We find that molecules that perturb these organisms are plentiful and that there is a great diversity of target pathways and proteins.

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To explore this phenomenon in greater detail we have initiated screens against:

  • the yeast Saccharomyces cereviciae,
    in collaboration with Dr. Leah Cowen
  • the fruit fly Drosophila melanogaster,
    in collaboration with Dr. Craig Smibert
  • the round worm Caenorhabdus elegans,
    in collaboration with Dr. Peter Roy

Exploring the chemical biology of lesser known organisms

While the streptomycetes are critical to this field, they are not the only microbes that produce and respond to biologically active molecules.

Most recently, we have initiated project aimed at exploring the chemical biology of other organisms.

To this end we are investigating new organisms from two sources:

First, we have initiated projects aimed at the discovery of novel bacterial species from the sea. These include free-living and endosymbiotic microbes.

Second, we are exploring a remarkable genus of fungal microbes called “Cordyceps” which includes the organism that causes the bizarre “zombie ant” phenomenon. Our goal is to understand the biosynthetic potential and role of these organisms in nature.

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Join Our Lab

The lab is founded on a solid base of classical bacterial genetics and biochemistry  - however, we will use any technology available to us to address the problems that we are interested in including genome and transcriptome sequencing, mass spectrometry and small molecule NMR.

Students and postdocs with experience in microbiology, molecular biology, protein or small molecule biochemistry, computer science and bioinformatics, chemical synthesis, or any related field could find a home in our lively group.

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