I study antibiotic biosynthesis as a physiological phenomenon. Recent advances in experimental chemistry and biology make it is possible to analyze antibiotic biosynthesis on a scale and at a resolution previously unimaginable. My training in synthetic chemistry, protein biochemistry, and molecular genetics enables me to capitalize on the emerging opportunities in this interdiscplinary research area. With this broad expertise, I am prepared to carry out penetrating, "system-level" analyses of antibiotic production in vivo. The subject of my studies will be Streptomyces bacteria. These soil bacteria and their close relatives among the actinomycetes are best known as producers of nearly two-thirds of the 10,000 known antibiotics, many of which have tremendous value in clinical and veterinary medicine (e.g., FK506, tetracycline, bleomycin, doxorubicin, vancomycin, erythromycin, and avermectin). Since the 1950s, pharmaceutical companies have fermented these organisms on very large scales to produce many of our medicines. Accordingly, much is known about their genetics and physiology. However, there is much to be learned about the molecular mechanisms that enable and regulate antibiotic production in streptomycetes and actinomycetes in general. To advance knowledge of these mechanisms I will study the best-characterized actinomycete, Streptomyces coelicolor A3(2), which produces four chemically distinct antibiotics via discrete biosynthetic pathways. Much about this organism is known as it has been studied intensively for over half of a century. Its genome has been sequenced and powerful tools for systematic gene manipulation, transcription profiling, and proteome analyses of S. coelicolor have been developed. These tools have yielded important new insights into Streptomyces biology. Although the changes in gene expression during antibiotic production have been measured, the corresponding changes in the concentrations of metabolites have not been characterized. To illuminate these changes, I will develop methods that enable measurement of the flux of low-molecular weight metabolites into pathways for antibiotic production. In addition, I will synthesize compounds that are capable of perturbing metabolic flux. These tools will be used synergistically with established biochemical methods for transcriptomics and proteomics to generate a molecular resolution description of the changes in Streptomyces physiology during antibiotic production. These methods will also be useful in comparative analyses of wild-type Streptomyces strains and those optimized by the pharmaceutical industry for the production of large quantities of antibiotics. These analyses are likely to reveal the cryptic physiological features associated with the over-production of antibiotics. Recognition of these features may suggest how streptomycetes can be rationally engineered for the production of large quantities of antibiotics.

Small molecules produced by organisms for chemical defense have long been exploited in medicine, biotechnology, and biological research. "CH0156: The Chemistry and Biology of Naturally Occurring Antibiotics" examines the origins, uses, modes of action, and preparations of some of the most important and useful of these 'antibiotic' molecules. Given the inter-disciplinary nature of this topic, this course is open to students with backgrounds in the biological and/or physical sciences. Familiarity with concepts of organic chemistry and biochemistry will be assumed.

Topics in Advanced Chemistry (CH0156)

• Babajide O. Okandeji and Jason K. Sello. "Brønsted Acidity of Substrates Influences the Outcome of Passerini Three Component Reactions". Journal of Organic Chemistry. 2009, 74, 5067-5070.
• Jesse B. Davis, J. Daniel Bailey, and Jason K. Sello. "A Biomimietic Synthesis of a New Class of Bacterial Signaling Molecules". Organic Letters, 2009, 11, 2984- 2987.
• James J. Vecchione, Blair Alexander, Jr. and Jason K. Sello. "Two Distinct Major Facilitator Superfamily Drug Efflux Pumps Mediate Chloramphenicol Resistance in Streptomyces coelicolor". Antimicrobial Agents and Chemotherapy. 2009. 53, 4673-7.
• James J. Vecchione and Jason K. Sello. "A Novel Tryptophanyl-tRNA Synthetase Gene Confers High Level Resistance to Indolmycin. Antimicrobial Agents and Chemotherapy, 2009, 53, 3972- 3980.
• Jennifer R. Davis and Jason K. Sello. "Regulation of Genes in Streptomyces Bacteria Required for Catabolism of Lignin-Derived Aromatic Compounds". Applied Microbiology and Biotechnology, 2009, accepted for publication.
• Jason K. Sello and Mark J. Buttner. "The Gene encoding Ribonuclease III Gene in Streptomyces coelicolor is Transcribed During Exponential Phase and is Required for Antibiotic Production and for Proper Sporulation". Journal of Bacteriology. 2008, 190, 4079-4083.
• Jason K. Sello and Mark J. Buttner. "The Oligoribonuclease Gene in Streptomyces coelicolor is not Transcriptionally or Translationally Coupled to adpA, a key bldA target". FEMS Microbiology Letters, 2008, 286, 60-65.
• Babajide O. Okandeji, Jonathan R. Gordon, Jason K. Sello. "Catalysis of Ugi Four Component Coupling Reactions by Rare Earth Metal Triflates". Journal of Organic Chemistry. 2008, 73, 5595-5597.
• James J. Vecchione and Jason K. Sello. "Characterization of an Inducible, Antibiotic-Resistant Aminoacyl-tRNA Synthetase Gene in Streptomyces coelicolor". Journal of Bacteriology. 2008, 190, 6253-6257.
• Michele Pacholec, Jason K. Sello, Michael G. Thomas, Christopher T. Walsh. "Formation of an Aminoacyl-S-Enzyme Intermediate is the First Committed Step in Chloramphenicol Biosynthesis". Org. Biomol. Chem. 2007, 5, 1692-1694.
• Jason K. Sello, Peter R. Andreana, Daesung Lee, Stuart L. Schreiber. "Stereochemical Control of Skeletal Diversity". Organic Letters, 2003, 5, 4125-4127.
• Daesung Lee, Jason K. Sello, Stuart L. Schreiber. "Pairwise Use of Complexity Generating Reactions in Diversity-Oriented Synthesis". Organic Letters, 2000, 2, 709-712.
• Daesung Lee, Jason K. Sello, Stuart L. Schreiber. "A Strategy for Macrocyclic Ring Closure and Functionalization Aimed Toward Split-Pool Syntheses". J. Am. Chem. Soc. 1999, 121, 10648-10649.
• Luis E. N. Quadri, Jason Sello, Thomas A. Keating, Paul H. Weinreb, Christopher T. Walsh. "Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin". Chemistry and Biology, 1998, 5, 631-645.