Sean F. Brady

Scholar: 2007

Awarded Institution
Professor Head, Laboratory of GeneticallyEncoded Small Molecules
The Rockefeller University


Research Interests

Genetically encoded small molecules play a wide variety of roles in biology and have proved useful in the development of small molecule therapeutic agents. Dr. Brady's research centers on the discovery, biosynthesis and characterization of new genetically encoded small molecules from microbial sources, with a special interest in the natural products of uncultured soil bacteria and those produced by pathogenic bacteria. He is also interested in the development of molecular tools that can be used to observe small molecules in vivo.

One of the key revelations to arise from the large-scale sequencing of bacterial genomic DNA is that traditional approaches used for the discovery of new natural products only provide functional access to a small fraction of the natural product biosynthetic gene clusters present in nature. These studies suggest that essentially all bacteria, from those that have not yet been cultured to those whose genomes have been completely sequenced, are rich sources of as-yet-unstudied natural product biosynthetic gene clusters. Using a range of molecular biology, organic chemistry and microbiological methods, Dr. Brady is interested in developing methods that can be used to access these previously inaccessible natural products.

Soil microbes that have not yet been cultured outnumber their cultured counterparts by at least two to three orders of magnitude. Uncultured bacteria are one of the largest remaining pools of genetic diversity that have not yet been examined for the production of natural products that could serve as molecular probes of biological processes and therapeutic agents. Dr. Brady's research first focuses on the development and application of new strategies for studying genetically encoded small molecules produced by uncultured bacteria. Although most bacteria are not readily grown in the laboratory, and it is thus not possible to characterize the natural products they produce using traditional microbiological methods, it is possible to extract microbial DNA directly from environmental samples and clone this DNA in easily cultured bacteria. Dr. Brady has worked extensively on the development of genetic strategies to access the vast chemical and biosynthetic potential of uncultured, and therefore previously inaccessible, bacteria. This has led to methods for both the construction of large libraries of DNA extracted from the environment (eDNA) and the screening of these libraries to access natural products encoded by the genomes of bacteria that are not easily cultured. These culture-independent methods are leading Dr. Brady to identify new natural products, biosynthetic enzymes and examples of bacterial signaling systems.

Dr. Brady's second focus, the chemistry of pathogenic bacteria, could one day help address the problem of drug-resistant bacteria. Pathogenic bacteria have evolved elaborate signaling systems and toxins that are crucial to their ability to initiate and maintain infections. The annotation of completely sequenced bacterial genomes has led to the identification of natural product biosynthetic gene clusters whose predicted products do not correspond to any molecules previously characterized from these organisms. Dr. Brady uses bioinformatics to examine genomes of sequenced bacteria in order to identify new gene clusters that might code for novel signaling molecules and toxins. Initially, he is focusing on studying pathways that resemble biosynthetic clusters known to code for small molecule signals. Studying the chemical networks of bacterial pathogens should provide new insights into molecules used in bacterial infections, and in turn, provide novel insights into how best to disrupt key steps in the establishment and propagation of bacterial infections.

The final area that Dr. Brady is working on is the development of general strategies for detecting small molecules in vivo. Studying the role of naturally occurring small organic molecules in biology is often difficult because there is a dearth of standard tools for visualizing and detecting these compounds in vivo. Generic systems that can be used to detect small molecules in vivo would be useful for studying the role small molecules play in complex biological processes as well as for controlling biological processes with these compounds.

Recipient of the Howard Hughes Medical Institute Early Career Scientist Award