Members of my research group and I have been investigating new approaches to antibacterial therapy and to biofuel production that are inspired by the unique metabolites and physiology of Streptomyces bacteria. A hallmark of my program has been the synergistic application of experimental methods from synthetic organic chemistry, molecular microbiology and biochemistry. Thematically, my research has been organized around potential solutions to challenges in human health and in energy.

Thematically, my research has been organized around potential solutions to challenges in medicine and in energy. Through our research, we have made significant contributions in bioenergy and in antibacterial drug development.

Solutions to Challenges in Human Health: We have pursued several lines of investigation on Streptomyces bacteria in parallel that concern antibiotic resistance, antibiotic production and antibacterial drug discovery.

Discovery of Antibiotic Resistance Genes via Genome Mining.
We propose that the drug development process can be refined by knowledge of the antibacterial resistance genes in bacterial populations. Specifically, a drug company may decide not pursue a particular antibacterial drug candidate if gene(s) that confer resistance to it are widely distributed in bacterial populations. It is our contention that one can discover resistance genes via analyzing the genomes of antibiotic-producing Streptomyces bacteria. In turn, bioinformatics can be used to identify homologs of these genes in pathogenic bacteria. The case study for our bioinformatic approach was the discovery of genes that confer resistance to indolmycin, a potent tryptophanyl-tRNA synthetase inhibitor that has frequently been mentioned as a drug candidate for treatment of bacterial infections. By mining the publicly available genome sequences of Streptomyces bacteria, we discovered a novel, auxiliary tryptophanyl-tRNA synthetase gene that confers resistance to indolmycin (Vecchione and Sello, 2009). Further, we determined that orthologs of this gene can be found in members of several bacterial species, including some human pathogens (Vecchione and Sello, 2009). Our efforts to analyze the expression of this auxiliary tryptophanyl-tRNA synthetase led to the discovery that the transcription of this gene is induced in the presence of indolmycin (Vecchione and Sello, 2008). We subsequently determined that the inducible transcription is mediated by a cis-acting RNA regulatory structure called ribosome-mediated attenuator (Vecchione and Sello, 2010).

Circumventing Multidrug Resistance in Bacteria.
Like many others, we have surmised that inhibition of drug efflux pumps could be a viable strategy for suppressing drug resistance phenotypes in human pathogens. Discovery of efflux pump inhibitors is challenging and we concluded that streptomycetes (which are known to harbor many drug efflux pumps) would be ideal organisms for screening putative inhibitors. To initiate work in this area, we established that the resistance of Streptomyces coelicolor to chloramphenicol is mediated by two distinct efflux pumps of the major facilitator superfamily (Vecchione et al., 2009). Subsequently, we found that the activity of chloramphenicol against S. coelicolor could be potentiated by Phe-Arg-β-napthylamide, a C-capped dipeptide that is a known inhibitor of resistance-nodulation-division family drug efflux pumps in Gram-negative bacteria. This observation was noteworthy because it was the first time that this compound had been reported to potentiate drug activity against a Gram-positive bacterium (Vecchione et al., 2009). Encouraged by the potentiation activity of Phe-Arg-β-napthylamide, we synthesized a library of structurally related C-capped dipeptides using the Ugi four component reaction and screened it for potentiators of chloramphenicol activity against S. coelicolor (Okandeji et al., 2011). The Ugi reaction was purposefully selected because of our experience with it in mechanistic studies of multicomponent reactions (Okandeji et al., 2008; Okandeji, 2009; Carney, et al., 2011). Ultimately, we identified a C-capped dipeptide that was an eight-fold potentiator of chloramphenicol activity against S. coelicolor than Phe-Arg-β-napthylamide (Okandeji et al., 2011). Corollary mechanistic studies proved that the molecular mechanism of potentiation was the inhibition of both chloramphenicol efflux pumps in S. coelicolor.

Improving Antibacterial Agents via Chemical Synthesis.
We have been working on projects directly related to the synthesis and discovery of novel antibacterial drugs. Again, our research is inspired by antibiotics produced by Streptomyces bacteria. One group of compounds in which we have been interested are the enopeptins. These acyldepsipeptidolactones (ADEPs) are of interest because they have a mode of action that is completely distinct from any known antibacterial drug- they bind and activate the bacterial protease ClpP. Because of their unique mode of action, they have activity against multi-drug resistant human pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci species (VRE). The enopeptins have poor pharmacological properties, but scientists at Bayer Healthcare used medicinal chemistry to generate an enopeptin analog (ADEP 4) with dramatically enhanced antibacterial potency and pharmacological efficacy. We proposed that the activity of ADEP4 could be improved by introducing conformationally constrained amino acids into the macrocyclic core structure. To simplify a route for preparation of ADEP 4 and analogs thereof based on the principles of conformational analysis, we developed a diversity-oriented route synthetic scheme featuring multicomponent reactions (i.e., the Ugi four component reaction and the Joullié-Ugi three component reaction) (Socha et al., 2010). Again, this synthetic route was selected based on our studies of multicomponent reactions (Okandeji et al., 2008; Okandeji and Sello, 2009, Carney, et al., 2011). Of the ten rationally designed analogs that we prepared, one of them exhibited more antibacterial activity than the parent compound. A provisional patent application on the compound and on our synthetic scheme has been filed by the Brown Technology Ventures Office.

Exploiting Chemical Communication for Enhancement of Antibiotic Production.
Two-thirds of the antibiotics used in clinical and veterinary medicine are produced by fermentation of Streptomyces bacteria. Improving the yields of fermentations would in principle lower the cost of drugs. We proposed that the Streptomyces bacteria in fermentations could be coaxed into producing more antibiotics by the addition of their chemical messengers that induce antibiotic production. To this end, we synthesized streptomycete messengers of the three major structural classes. My research group reported the first syntheses of two most recently identified structural classes of Streptomyces chemical messengers- the methylenomycin furans produced by Streptomyces coelicolor and the pimaricin-inducing factor from Streptomyces natalensis (Morin et al., 2009; Davis and Sello, 2010). Further, we achieved the shortest synthesis of A-factor, an inducer of streptomycin production in Streptomyces griseus, by replicating reactions in the biosynthesis (Morin et al., 2012). In addition to exploring the practical utility of these molecules, we are using these molecules to understand the complex, small molecule lexicon of Streptomyces bacteria.

Probing and Enhancing Antibiotic Production in Streptomyces bacteria.
Our efforts to engineer Streptomyces bacteria for the overproduction of antibiotics have been based on fundamental studies of their physiology. In this context, we have studied the ribonuclease III gene of S. coelicolor, which is essential for antibiotic production (Sello and Buttner, 2008). In a separate study, we serendipitously discovered that disruption of the gene encoding the translational GTPase elongation factor 4 enhanced the production of the calcium-dependent antibiotic in Streptomyces coelicolor (Badu-Nkansah and Sello, 2010). This was the first gene disruption reported to enhance production of the calcium-dependent antibiotic. We speculate that disruption of the elongation factor 4 gene could be a general strategy for enhancing antibiotic production in Streptomyces bacteria.
To facilitate holistic studies of metabolic flux underlying antibiotic biosynthesis, we have developed new tools for derivatizing metabolites in ways that facilitate analysis (Totaro, et al. 2012). We anticipate that these tools will be useful in holistic studies of metabolism (i.e., metabolomics) and in clinical chemistry.

Solutions to Challenges in Energy: To address the energy problem, we have been working on sustainable methods for producing biofuels based on organic chemistry and microbial metabolism.

A Microbial Platform for Conversion of Plant Biomass into Biofuels.
In the context of sustainable energy, we have been exploring ways in which we can harness the catabolic capabilities of Streptomyces bacteria for the conversion of plant biomass into biofuels. Much of our research in this area is supported by a National Science Foundation Career Award and a Seed Award from the Office of the Vice President for Research at Brown University. In one project, we have sequencing and analyzing the genomes of actinomycetes known to degrade plant biomass (i.e., Amycolatopsis orientalis and Streptomyces viridosporus) in a Department of Energy funded collaboration with the Joint Genome Institute. Our objective in this project is to identify and characterize all of the components of the machinery that enable the degradation and consumption of the lignin, cellulose, and hemicellulose components of plant biomass. We have been particularly interested in the catabolism of lignin. In this context, we have been investigating the regulation of a gene cluster in S. coelicolor and other streptomycetes encoding enzymes that catabolize lignin-derived aromatic compounds. We identified a transcription factor that acts as a negative regulator of the gene cluster (Davis and Sello, 2010).

New Chemical Methods for the Production and Analysis of Biodiesel.
In combination with the microbial work, we have been developing new chemical methods for the conversion of fatty acids and triglycerides into biodiesel. Our work in this area has been inspired by the problem that the current methods for biodiesel production utilize corrosive and environmentally harmful reagents (i.e., potassium hydroxide and sulfuric acid). As an alternative, we demonstrated that the air- and moisture-insensitive Lewis acid catalysts scandium triflate and bismuth triflate promote biodiesel-forming reactions (i.e., esterification of fatty acids and trans-esterification of triglycerides) in a microwave reactor (Socha and Sello, 2010). Our chemistry is much more environmentally benign than the methods used historically for the production of biodiesel. We have filed a provisional patent application on this method and the Brown Technology Ventures Office is exploring licensing agreements with bioenergy companies. In collaboration with Prof. Paul G. Williard in the Department of Chemistry at Brown, we demonstrated that diffusion ordered NMR spectroscopy can be used to analyze both biodiesel and biodiesel forming reactions (Socha, et al., 2010)

Current Research Support:

National Science Foundation Career Award, "Bacterial Catabolism of Plant Biomass- A Phenomenon with Special Relevance to Bioenergy and Environmental Science" (PI: J. K. Sello.)

National Institutes of Health PO1 Grant, “Project #2: Mechanisms Controlling Neuroinvasion of Brain Cells by JCPYV” (PI: W. J. Atwood, sub-contract to J. K. Sello)

Lara Hull Trust, “Development of Inhibitors of the 20S Proteasome in Mycobacterium tuberculosis” (PI: Jason K. Sello)

Air Force, Department of Defense, “Development of Efflux Pump Inhibitors to Suppress Growth of Bacteria in Jet Fuel Tanks” (PI: Jason K. Sello)

Past Research Support:

 

Brown university, Office of the Vice President Seed Award, (Co PIs: J. K. Sello, R. Page and C. Lawrence)

Department of Energy, Community Sequencing Project, "Sequencing the Genomes of Amycolatopsis orientalis and Streptomyces viridosporus, Plant Biomass Degrading Bacteria" (PI: J. K. Sello, no funds sent to Brown University in collaboration with the Joint Genome Institute)

National Science Foundation Research Initiation Grant "Harnessing Streptomyces bacteria as Lignocellulose Biorefineries" (PI: J. K. Sello, 8/2009-7/2011)

Salomon Research Grant, Office of Vice President for Research, Brown University, "Development of New Chemical Methods for the Analysis of Proteins and Metabolites in Biological Samples," (PI: Jason K. Sello Ph.D.)

Brown University, Department of Chemistry. "Frontiers in Chemistry Award" (PI: J. K. Sello, (Jan. 1– Dec. 31, 2008)

Burroughs Wellcome Fund, Career Award at the Scientific Interface.

Davis, J. R., Brown, B. L., Page, R., Sello, J. K. (2013) "Study of PcaV from Streptomyces coelicolor Yields New Insights into Ligand-Responsive MarR Family Transcription Factors". Nucleic Acids Research. 41: 3888-900. PMID: 23396446

Davis, J. R., Goodwin, L., Teshima, H., Detter, C., Tapia, R., Han, C., Huntemann, M., Wei, C.-L., Han, J., Chen, A, Kyrpides, N., Mavrommatis, K., Szeto, E., Markowitz, V., Ivanova, N, Mikhailova, N., Ovchinnikova, G., Pagani, I., Pati, A., Woyke, T., Pitluck, S., Peters, L., Nolan, M., Land, M., Sello, J.K. (2013) "Genome Sequence of Streptomyces viridosporus T7A ATCC 39115, a Lignin-Degrading Actinomycete". Genome Announcements, 1(4): e00416-13. PMID: 23833133.

Compton, C. L., Schmitz, K. R., Sauer, R. T. Sello, J. K. (2013) "Antibacterial of and Resistance to Small Molecule Inhibitors of the ClpP Peptidase". ACS Chemical Biology, Epub Ahead of Print. PMID: 24047344

Nelson, C., Carney, D. W., Derdowski, A, Lipovsky, A, Gee, G., O'Hara, B., Williard, P., DiMaio, D., Sello, J. K., Atwood, W. (2013) "A retrograde trafficking inhibitor of ricin and shiga-like toxins inhibits infection of cells by human and monkey polyomaviruses". mBio, accepted.

Morin, J., Adams, K. L., Sello, J. K. (2012) "Efficient Synthesis of the γ-butyrolactone Autoinducer of Streptomyces griseus via Replication of Biosynthetic Reactions". Organic and Biomolecular Chemistry, 10: 1517-20. PMID: 22246070

Davis, J. R. Goodwin, L. A., Woyke, T. Teshima, H., Bruce, D., Detter, C., Tapia, R., Han, S., Han, J., Pitluck, S., Nolan, M., Mikhailova, N., Land, M. L. Sello, J.K. (2012) "Genome Sequence of Amycolatopsis sp. ATCC 39116, a Plant Biomass-Degrading Actinomycete". Journal of Bacteriology, 194:2396-7. PMID: 22493203

Totaro, K. A., Okandeji, B.O., Sello, J. K. (2012) "Use of a Multicomponent Reaction for Chemoselective Derivatization of Multiple Classes of Metabolites". ChemBiochem, 13: 987- 991. PMID: 22505051

Sello, J. K. (2012) "Mining the Antibiotic Resistome". Chemistry & Biology. 19: 1220-1221. PMID: 23102216

Okandeji, B. O., Greenwald, D. M., Wroten, J., Sello, J. K. (2011) "Synthesis and Evaluation of Inhibitors of Drug Efflux Pumps of the Major Facilitator Superfamily in Bacteria". Bioorganic and Medicinal Chemistry, 19:7679-89. PMID: 22055717

Carney, D., Truong, J., Sello, J. K. (2011) "Investigation of the Configurational Stabilities of Chiral Isocyanoacetates in Multicomponent Reactions". Journal of Organic Chemistry. 76: 10279-10285. PMID: 22044401

Davis, J. R. and Sello, J. K. (2010) "Regulation of Genes in Streptomyces Bacteria Required for Catabolism of Lignin-Derived Aromatic Compounds". Applied Microbiology and Biotechnology, 86:921-9. PMID: 20012281

Vecchione, J. J. and Sello, J. K. (2010) "Regulation of an Auxiliary, Antibiotic-Resistant Tryptophanyl-tRNA Synthetase Gene via Ribosome-Mediated Transcriptional Attenuation". Journal of Bacteriology, 192, 3565-3573. PMID: 20453096

Morin, J. B. and Sello, J. K. (2010) "Efficient Synthesis of a Peculiar Vicinal Diamine Pheromone from Streptomyces natalensis". Organic Letters, 12, 3522-3524. PMID: 20670016

Socha, A. M., Kagan, G., Li, W., Hopson, R. W., Sello, J. K., and Williard, P. G. (2010) "Diffusion coefficient-formula weight correlation analysis via DOSY NMR to examine acylglyceride mixtures and biodiesel production". Energy and Fuels, 24, 2518-2521.

Socha, A. M. and Sello J. K. (2010) "Efficient Conversion of Triacylglycerols and Fatty acids into Biodiesel in a Microwave Reactor Using Metal Triflate Catalysts". Organic and Biomolecular Chemistry, 8, 4753-4756. PMID: 20714659

Socha, A. M., Tan, N. Y-M., LaPlante, K. and Sello J. K. (2010) "Diversity-Oriented Synthesis of Cyclic Acyldepsipeptides Leads to the Discovery of a Potent Antibacterial Agent". Bioorganic and Medicinal Chemistry, 18, 7193-7202. PMID: 20833054

Badu-Nkansah, A. and Sello, J. K. (2010) "Deletion of the Elongation Factor 4 Gene (lepA) in Streptomyces coelicolor Enhances the Production of the Calcium-Dependent Antibiotic". FEMS Microbiology Letters, 311, 146-151. PMID: 20735483

Okandeji, B. O. and Sello, J. K. (2009) "Brønsted Acidity of Substrates Influences the Outcome of Passerini Three Component Reactions". Journal of Organic Chemistry. 74, 5067-5070.

Davis, J. B., Bailey, J. D., and Sello, J. K. (2009) "A Biomimetic Synthesis of a New Class of Bacterial Signaling Molecules". Organic Letters, 11, 2984- 2987. PMID: 19545145

Vecchione, J. J., Alexander, B. Jr. and Sello, J. K. (2009) "Two Distinct Major Facilitator Superfamily Drug Efflux Pumps Mediate Chloramphenicol Resistance in Streptomyces coelicolor". Antimicrobial Agents and Chemotherapy, 53, 4673-7. PMID: 19687245

Vecchione, J. J. and Sello, J. K. (2009) "A Novel Tryptophanyl-tRNA Synthetase Gene Confers High Level Resistance to Indolmycin, Antimicrobial Agents and Chemotherapy". 53, 3972- 3980. PMID: 19546369

Sello, J. K. and Buttner, M. J. (2008) "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, 190, 4079-4083. PMID: 18359817.

Okandeji, B. O., Gordon, J. R., and Sello, J. K. (2008) "Catalysis of Ugi Four Component Coupling Reactions by Rare Earth Metal Triflates". Journal of Organic Chemistry. 73, 5595-5597. PMID: 18570401

Vecchione, J. J. and Sello, J. K. (2008) "Characterization of an Inducible, Antibiotic-Resistant Aminoacyl-tRNA Synthetase Gene in Streptomyces coelicolor". Journal of Bacteriology, 190, 6253-6257. PMID: 18621902

Sello, J. K. and Buttner, M. J. (2008) "The Oligoribonuclease Gene in Streptomyces coelicolor is not Transcriptionally or Translationally Coupled to adpA, a key bldA target". FEMS Microbiology Letters, 286, 60-65. PMID: 18625025

2012 "Very Important Paper" in ChemBiochem (February 2012)
2011 National Science Foundation Career Award (5 years)
2011 Invited Co-Chair, Chemical Biology and Biocatalysis Session, American Society of Biochemistry and Molecular Biology National Meeting (San Diego, April 2012)
2011 Seed Fund Award (w/ Profs. Charles Lawrence and Rebecca Page), Office of Vice President of Research, Brown University
2011 Discussion Leader at Bioorganic Gordon Conference
2011 ASBMB Minority Spotlight Scientist for Month of March
2011 Invited Co-Chair and Speaker at Chemical Biology and Catalysis Session of the 2012 national meeting of the American Society of Biochemistry and Molecular Biology
2011 Co-chair and Speaker at Evolution of Antibiotic Resistance session, "16th International Symposium on the Biology of Actinomycetes" (Puerto Vallarta, Mexico)
2010 Top-Ten Most Accessed Papers in "Organic and Biomolecular Chemistry" in the month of October.
2010 Invited Lecture, Young Investigator Symposium at National Meeting of the American Chemical Society, Boston, MA
2009 Best Poster in Natural Products Section, Society for Industrial Microbiology Meeting (presented by Jesse Davis Morin)
2009 Brown University Swearer Center Engaged Scholar Award
2008 Discussion Leader at the Enzymes Gordon Conference
2008 Frontier in Chemistry Award, Department of Chemistry, Brown University
2008 Recipient of R. B. Salomon Award, Brown University, OVPR
2003 Burroughs Wellcome Fund Career Award at the Scientific Interface
2002-2004 Merck-UNCF Postdoctoral Research Fellowship
2000 Certificate of Distinction in Teaching for "Biological Sciences 1: Introduction to Molecular Biology," Harvard University
1997 Pre-doctoral Fellowship, National Science Foundation
1998 Glaxo-Wellcome-UNCF Scientific Achievement Award
1997 Magna cum laude graduate, Morehouse College
1997 Phi Beta Kappa, Morehouse College
1997 J. K. Haynes Award for Outstanding Senior Biology Major
1993 - 1997 Dean's List, Morehouse College

American Chemical Society
American Society for Microbiology
American Society for Biochemistry and Molecular Biology
Society for Industrial Microbiology

The convergence of the physical and life sciences is especially apparent today. Dramatic changes in the curricula of chemistry and biology are needed to prepare future scientists for interdisciplinary research. Generally, students take a battery of courses that deal with the sub-disciplines of either chemistry (i.e., organic chemistry, inorganic chemistry, physical chemistry, theoretical chemistry, and analytical chemistry) or biology (i.e., biochemistry, genetics, developmental biology, ecology, cell biology, physiology). It is my conviction that today's teacher-scholars in the chemical sciences must show students the connections between the physical and life sciences. I have developed a pedagogical strategy derived from my interdisciplinary research background and wide-ranging interests that allows me to teach sub-disciplines of both chemistry and biology in an integrated fashion.

I designed and taught a new course offered by the Department of Chemistry entitled the "Chemistry and Biology and Naturally Occurring Antibiotics." My objective was to highlight the inextricable links between chemistry and biology in a way that would capture the attention and imagination of advanced undergraduates and first-year graduate students. I chose antibiotics as a pedagogical vehicle for several reasons. First, antibiotics are a topic with which students are conceptually familiar. They are well aware of the incalculable impact that antibiotics have on human health via their use as antibacterial agents, anticancer agents, antitumor drugs, and immunosuppressants. Second, antibiotics are structurally complex small molecules produced by microorganisms, presumably with important ecological roles. Third, many antibiotics interfere in defined ways with fundamental biological processes such as DNA replication, protein synthesis, and cell wall biosynthesis by perturbing the functions of essential proteins. Finally, many ideas about the structure and reactivity of organic compounds have been gained from efforts to synthesize antibiotics and characterize their biosynthesis. Through antibiotics, I found a fantastic and innovative way to coherently integrate fundamental concepts in microbiology, molecular structure, reaction mechanisms, strategies in target-oriented organic synthesis, enzymology, genetics, cell biology, and biotechnology. These topics are usually taught in separate courses at Brown and at many other universities.

In addition to my antibiotics course, I have taught in support of the required curriculum of the Department of Chemistry at Brown University. For four consecutive years, I taught "CHEM 360: Organic Chemistry II". The course covers traditional concepts in organic chemistry like molecular structure, proposal of reaction mechanism, and the synthesis of complex molecules. I took a decidedly problem-solving perspective in leading this course. I have also taught "CHEM 1240: Biochemistry". In this course, I covered the major metabolic pathways and the structures and mechanisms of the corresponding enzymes. The students were implored to learn the molecular logic of chemical transformations underlying biological phenomena, rather than memorizing the structures of metabolites and the names of enzymes. I also taught a semester long seminar "CHEM 08: Drug Discovery in the Pharmaceutical Industry" in 2009 for first year undergraduates. This course was designed to help students in the earliest stage of their academic career appreciate the history of medicine and the connections between chemistry and biology.

I fervently believe that a critical part of teaching is mentoring young scientists at all levels. In conjunction my classroom-based instruction, I have mentored a post-doctoral fellow, nine graduate students, and twenty-six undergraduates in research over the past five years. The advising of students has taken place in weekly group meetings and in daily or weekly meetings with students. In every interaction, I encourage students to take ownership over their projects and to think critically about experimental design and the interpretation of their results.