Dr. Bradley Moore: Drug Discovery

Research Summary: Natural Product Engineering

Dr. Moore’s laboratory is focused on understanding the fundamental mechanisms and pathways involved in how bacteria produce antibiotics, anticancer agents, and other bioactive natural products, with a special emphasis on marine microorganisms. Research is performed at the chemistry-biology interface and involves a number of sophisticated approaches that include heterologous biosynthesis, mutasynthesis, chemoenzymatic total synthesis, genome mining, and in vitro and in vivo biochemical analysis. Biosynthetic systems are largely targeted from marine actinomycete bacteria, which harbor promising natural product compounds such as the potent anticancer agent salinosporamide A, the polyketide antibiotics enterocin and marinopyrrole, and the cyclomarin anti-inflammatory peptides.

Microbial biodiversity remains one of the last great biotic frontiers, and developing effective strategies to discover and exploit new small molecules from this resource is integral to the success of future drug discovery efforts. The introduction of recombinant technology to the natural product discovery process has allowed us to interrogate and manipulate biosynthetic processes in order to expand the biosynthetic capabilities of marine bacteria to yield new chemical entities for biological evaluation.

Academic Achievements

Education: B.S. in Chemistry (1989) University of Hawaii; Ph.D. in Bioorganic Chemistry (1994) University of Washington.

Awards and Honors: ASP Matt Suffness New Investigator Award (2001); NIH SBCB Study Section founding member (2005-2008); Commissioning Editor of Natural Product Reports (2005-present); Novartis-MIT Lecturer in Organic Chemistry (2009- 2010).

Teaching

• Contemporary Topics in Pharmacology (SPPS 218A, B).
• Pharmaceutical Chemistry (SPPS 221).
• Pharmaceutical Biochemistry (SPPS 223).
• Seminar in Marine Natural Products (SIO 262).
• Special Topics in Marine Natural Products (SIO 264).

Key Contributions to Pharmaceutical Sciences

• Pioneered the biosynthesis and bioengineering of marine bacterial natural product drugs.
• Sequenced and characterized the first complete marine actinomycete genomes.
• Developed metabolic engineering and synthetic biology techniques for the rational production of new chemical entities.
• Discovered antibiotic biosynthesis enzymes and elucidated their mechanistic enzymology.

Selected Recent Publications (from >85 peer-reviewed articles)

Udwary et al. (2007). Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. PNAS 104:10376- 10381.

Cheng et al. (2007). Enzymatic total synthesis of enterocin polyketides. Nat. Chem. Biol. 3:557-558.

Eustaquio et al. (2008). Discovery and characterization of a marine bacterial SAM- dependent chlorinase. Nat. Chem. Biol. 4:69-74.

McGlinchey et al. (2008). Engineered biosynthesis of antiprotealide and other unnatural salinosporamide proteasome inhibitors. J. Am. Chem. Soc. 130:7822- 7823.

Eustaquio et al. (2009). Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-CoA from S-adenosyl-L- methionine. PNAS. 106:12295-12300.

Nett et al. (2009). Function-oriented biosynthesis of β-lactone proteasome inhibitors in Salinispora tropica. J. Med. Chem. 52:6163-6167.

Potential Collaborative Programs with the Pharmaceutical Industry

• 15 years experience in the discovery and application of natural products and their biosynthetic enzymes and genes.
• Broad array of chemical, biochemical and molecular genetic approaches to understanding and bioengineering the biosynthesis of natural product drugs.