Natural products discovery in the post-genomics era
Natural products, also known as secondary metabolites, are small molecules produced by a variety of plants, animals, and microorganisms that have found tremendous societal value in medicine, agriculture, food production, and energy. One surprising revelation of the past decade of genome sequencing efforts is that many organisms contain the biosynthetic potential for dozens of new natural products that are not produced during normal laboratory cultivation. Our group is developing new tools and strategies to access this largely untapped resource for chemical diversity and to engineer the relevant metabolic pathways for increased production. We are leveraging the latest DNA synthesis and assembly technologies to uncover new enzymatic reactions and explore novel methods for evolving biosynthetic pathways in the lab.
Precision engineering of diverse bacterial species
While our ability to achieve fine-tuned control over gene expression in model organisms such as Escherichia coli or Saccharomyces cerevisiae has taken large strides in the past decade, these organisms represent only a tiny fraction of the microbial kingdom. Our group is developing new methods to allow precision genetic engineering of a broader swath of the tree of life, with the aim of harnessing unique biological capabilities of poorly understood organisms.
Smanski MJ, Bhatia S, Park YJ, Zhao D, Giannoukos G, Ciulla D, Busby M, Calderon J, Nicol R, Gordon DB, Densmore D, Voigt CA (2014) "Combinatorial design and fabrication of refactored gene clusters." in revision.
Peterson RM, Huang T, Rudolf JD, Smanski MJ, Shen B (2013) "Mechanisms of self-resistance in the platensimycin and platencin producing Streptomyces platensis MA7327 and MA7339 strains." Chemistry and Biology **Paper highlighted in The Scientist Magazine: Akst, J (2014) "How a microbe resists its own antibiotics." The Scientist (2/20/2014)
Yu Z, Rateb ME, Smanski MJ, Peterson RM, Shen B (2013) "Isolation and structural elucidation of glucoside congeners of platencin from Streptomyces platensis SB12600." J. Antibiotics 66:291-294.
Smanski MJ, Casper J, Peterson RM, Yu Z, Rajski SR, Shen B (2012) "Expression of the platencin biosynthetic gene cluster in heterologous hosts yielding new platencin congeners." J. Nat. Prod. 75:2158-2167.
Smanski MJ, Peterson RM, Shen B (2012) "Platensimycin and platencin biosynthesis in Streptomyces platensis showcasing discovery and characterization of novel diterpene synthases." Methods Enzymol. 515:163-186.
Smanski MJ, Peterson RM, Huang S-X, Shen B (2012) "Bacterial diterpene synthases: new opportunities for mechanistic enzymology and engineered biosynthesis." Curr. Opin. Chem. Biol. 16:132-141.
Smanski MJ, Qu X, Liu W, Shen B (2012) "Biosynthesis of pharmaceutical natural products and their pathway engineering." Chapter 4 in Breakthroughs and Perspectives in Organic Chemistry. Ding K, Dai L eds., Wiley-VCH, 125-178.
Smanski MJ, Yu Z, Casper J, Lin S, Peterson RM, Chen Y, Wendt-Pienkowski E, Rajski SR, Shen B (2011) "Dedicated ent-kaurene and ent-atiserene synthases for platensimycin and platencin biosynthesis." Proc. Natl. Acad. Sci. USA 108:13498-13503. **Paper highlighted in Chemical & Engineering News: Borman, S (2011) Natural product synthases analyzed. C&EN 89:31.
Chen Y, Smanski MJ, Shen B (2010) "Improvement of secondary metabolite production in Streptomyces by manipulating pathway regulation." Appl. Microbiol. Biotechnol. 86:19-25.
Yu Z, Smanski MJ, Peterson RM, Marchillo K, Andes D, Rajski SR, Shen B (2010) "Engineering of Streptomyces platensis MA7339 for overproduction of platencin and congeners." Org. Lett. 12:1744-1747.
Smanski MJ, Peterson RM, Rajski SR, Shen B (2009) "Engineered Streptomyces platensis strains that overproduce antibiotics platensimycin and platencin." Antimicrob. Agents Chemother. 53:1299-1304.