Heads of Laboratories
Tri-Institutional Associate Professor, Evnin Associate Professor
Laboratory of Genetically Encoded Small Molecules
Natural products — or more specifically, genetically encoded small molecules — play a wide variety of roles in biology and have proved very useful in the development of therapeutic agents. Dr. Brady’s research centers on the discovery and characterization of new, genetically encoded small molecules from microbial sources, with a special focus on those produced by uncultured soil bacteria, human commensal bacteria, and pathogenic bacteria.
One of the key revelations from the large-scale sequencing of bacterial genomic DNA is that the approaches traditionally used for identifying new natural products only provide access to a small fraction of the biosynthetic gene clusters present in nature. These studies indicate that essentially all bacteria — from those with fully sequenced genomes to those not yet cultured — are rich sources of unstudied natural products. Using methods from molecular biology, organic chemistry, and microbiology, Dr. Brady is working to access the biosynthetic gene clusters responsible for these previously inaccessible natural products.The development of methods to do so should significantly increase the number and diversity of natural products available to test as probes of biological processes and therapeutic agents.
Dr. Brady’s first research focus is the development of new strategies for studying genetically encoded small molecules produced by bacteria that have not been grown in the lab. Soil microbes that have not yet been cultured outnumber their cultured counterparts by at least two to three orders of magnitude. As such, uncultured bacteria are one of the largest pools of genetic diversity that remain unexamined for potentially useful natural products. Dr. Brady has worked extensively on the development of genetic strategies to access the vast chemical and biosynthetic potential of uncultured bacteria, extracting this previously inaccessible DNA directly from environmental samples and cloning it in easily cultured bacteria.
This approach has allowed for the construction of large libraries of environmental DNA, as well as the development of methods to screen these libraries. Dr. Brady’s work has shown that these libraries are a promising source of both new derivatives of pharmacologically important classes of natural products, as well as completely novel families of bioactive natural products.
His group has begun mapping the presence of promising microbial gene clusters found in soil samples collected around the world. These maps may help guide the discovery of natural products by directing investigators to certain regions and environments.
The second focus of the Brady lab, the chemistry of human microbiome-associated and pathogenic bacteria, could one day help to understand how commensal bacteria interact with their human hosts and potentially address the problem of drug-resistant pathogenic bacteria. Dr. Brady uses phenotypic screening methods as well as bioinformatics methods to examine the small molecules produced by commensal and pathogenic bacteria. By studying the complex collections of small molecules used by these bacteria, he hopes to gain new insight into how bacteria interact with the world around them and, in turn, determine how to better control both commensal and pathogenic bacteria.
B.A. in molecular biology, 1993
M.S. in organic chemistry, 1999
Ph.D. in organic chemistry, 2002
Cornell University, 2002
Harvard Medical School
Assistant Professor, 2006–2012
Associate Professor, 2012–
The Rockefeller University
Early Career Scientist, 2009–2015
Howard Hughes Medical Institute
Sinsheimer Fund Scholar, 2007
Beckman Young Investigator, 2007
Irma T. Hirschl/Monique Weill-Caulier Trust Research Award, 2007
Searle Scholar, 2007
Kenneth Rainin Foundation Innovator Award, 2013
Owen, J.G. et al. Multiplexed metagenome mining using short DNA sequence tags facilitates targeted discovery of epoxyketone proteasome inhibitors. Proc. Natl. Acad. Sci. U.S.A. 112, 4221–4226 (2015).
Charlop-Powers, Z. et al. Global biogeographic sampling of bacterial secondary metabolism. eLife 4, e05048 (2015).
Biggins, J.B. et al. The chemical arsenal of Burkholderia pseudomallei is essential for pathogenicity. J. Am. Chem. Soc. 136, 9484–9490 (2014).
Kang, H.S. and Brady, S.F. Arimetamycin A: improving clinically relevant families of natural products through sequence guided screening of soil metagenomes. Angew. Chem. Int. Ed. Engl. 52, 11063–11067 (2013).
Chang, F.Y. and Brady, S.F. Discovery of indolotryptoline antiproliferative agents by homology-guided metagenomic screening. Proc. Natl. Acad. Sci. U.S.A. 110, 2478–2483 (2013).
Dr. Brady is a faculty member in the David Rockefeller Graduate Program, the Tri-Institutional M.D.-Ph.D. Program, and the Tri-Institutional Ph.D. Program in Chemical Biology.