University of Tuebingen
Auf der Morgenstelle 28
72076 Tuebingen, Germany
NATURAL PRODUCT DISCOVERY, SYNTHESIS,
AND CHEMICAL BIOLOGY
The Hughes Research Group specializes in microbial natural product discovery, synthesis, and chemical biology. We have characterized scores of natural products (NPs) using a combination of NMR spectroscopy and mass spectrometry, we have completed several total syntheses, and we have identified the cellular targets of numerous secondary metabolites.
We also develop derivatization strategies to discover new NPs in extracts. The method, called reactivity-guided isolation or chemical labeling, identifies metabolites based on their reactivity and has the potential to transform the way in which natural products chemists uncover certain classes of NPs. Specifically, the approach entails the covalent labeling of targeted NPs using chemoselective reagents or “probes” with prominent UV/vis properties and a distinct bromine or chlorine isotopic signature and is tied to the well-established practice of using reactive bromoarenes such as 4-bromobenzoyl chloride to yield crystalline material amenable to X-ray crystal structure analysis. Despite the fact that it does not directly furnish unaltered NPs, the method provides profound insight into the chemical space of an extract. It is a precise examination into the presence and abundance of a specific functionality or structural moiety that can be directly coupled to genome-mining studies. The method promises to de-orphan a large number of biosynthetic gene clusters and lead to the discovery of new NPs in a chemocentric manner.
To date, we have designed and applied probes that target NPs with electrophilic moieties (epoxides, α,β-unsaturated carbonyl groups, β-lactones, β-lactams), conjugated alkenes, terminal alkynes, enediynes, isocyanides, phosphonates, and amino groups.
The thiol probes
Target: epoxides, α,β-unsaturated carbonyl groups, β-lactones, β-lactams
The nitrosopyridine probe
Target: conjugated alkenes
The azide probe
Target: terminal alkynes
The tetrazine probe
The diazo probe
CHAMBERS C. Hughes
Dr. Hughes was born and raised in bucolic western New York, USA. In 1999 he graduated with a B.S. in biochemistry and a minor in Latin from Geneseo College. In 2004 he completed a Ph.D. in chemistry from the University of California, Berkeley. There, he worked with Prof. Dirk Trauner on the chemical synthesis of two terrestrial and two marine natural products. Chambers was the first member of the then-nascent Trauner research group to earn a doctorate. Next, Dr. Hughes held an extended postdoctoral/research associate appointment with Prof. William Fenical at the Scripps Institution of Oceanography, UC San Diego. During this time, he led efforts in the discovery, synthesis, and chemical biology of several marine-derived bacterial natural products. In 2012 Hughes was hired as assistant professor at Scripps. He then joined his family, in 2019, in Tübingen and is currently a Research Group Leader in the Department of Microbial Bioactive Compounds at the University of Tübingen.
1997–1999 Geneseo College (SUNY)
Research assistant (Profs. Robert E. Rosenberg and David K. Johnson)
1999–2004 UC Berkeley
Graduate student (Profs. Dirk Trauner and David W. C. MacMillan)
2005–2012 Scripps Institution of Oceanography, UC San Diego
Postdoctoral scholar/Research associate IV (Prof. William Fenical)
2012–2019 Scripps Institution of Oceanography, UC San Diego
Assistant Professor of Chemical Biology
2019– University of Tübingen
Research Group Leader
Friedhelm Albrecht, University of Tübingen
phone: +49(0) 7071-2974623
Julia Moschny, postdoctoral scholar
Pharm degree, University of Würzburg
Marita Wurm, technical assistant
Dipl. Biol., TU Kaiserslautern
Annika Esch, graduate student
B.A., University of Cambridge
M.Sci., University of Cambridge
Andreas Kulik, technical assistant
Dipl. Ing., Hochschule Reutlingen
(36) Hughes, C. C.* (2020) Chemical labeling strategies for small molecule natural product detection, isolation, and structure elucidation. Nat. Prod. Rep., submitted.
ASSISTANT PROFESSOR (SCRIPPS INSTITUTION OF OCEANOGRAPHY)
(35) Ding, Y., Murphy, K. M., Poretsky, E., Mafu, S., Yang, B., Char, S. N., Christensen, S. A., Saldivar, E., Wu, M., Wang, Q., Ji, L., Schmitz, R. J., Kremling, K. A., Buckler, E. S., Shen, Z., Briggs, S. P., Bohlmann, J., Sher, A., Castro-Falcon, G., Hughes, C. C., Huffaker, A., Zerbe, P., and Schmelz, E. A. (2019) Multiple genes recruited from hormone pathways partition maize diterpenoid defenses. Nat. Plants, 5, 1043–1056. [LINK]
(34) Seiler, G. S., and Hughes, C. C.* (2019) Progress toward the total synthesis of the lymphostins: Preparation of a functionalized tetrahydropyrrolo[4,3,2-de]quinoline and unusual oxidative dimerization. J. Org. Chem., 84, 9339–9343. [LINK]
(33) Moss, N. A., Seiler, G. S., Leão, T., Castro-Falcon, G., Gerwick, L., Hughes, C. C., and Gerwick, W. H. (2019) Nature’s combinatorial biosynthesis produces vatiamides A-F. Angew. Chem. - Int. Ed. 58, 9027–9031. [LINK]
(32) Kearney, S. E., Zahoránsky-Kőhalmi, G., Brimacombe, K. R., Henderson, M. J., Lynch, C., Zhao, T., Wan, K. K. …Hughes, C. C… Rohde, J. M. (2018) Canvass: A crowd-sourced, natural product screening library for exploring biological space. ACS Cent. Sci. 4, 1727–1741. [LINK]
(31) Castro-Falcon, G.,† Seiler, G. S.,† Demir, O., Rathinaswamy, M. K., Hamelin, D., Hoffmann, R. M., Makowski, S. L., Letzel, A.-C., Field, S. J., Burke, J. E., Amaro, R. E., and Hughes, C. C.* (2018) Neolymphostin A is a covalent phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor that employs an unusual electrophilic vinylogous ester. J. Med. Chem. 61, 10463–10472. [LINK]
(30) Castro-Falcon, G., Millán-Aguiñaga, N., Roullier, C., Jensen, P. R., and Hughes, C. C.* (2018) Nitrosopyridine probe to detect polyketide natural products with conjugated alkenes: Discovery of novodaryamide and nocarditriene. ACS Chem. Biol. 13, 3097–3106. [LINK]
(29) Patin, N. V., Floros, D. J., Hughes, C. C., Dorrestein, P. C., and Jensen, P. R. (2018) The role of inter-species interactions in Salinispora specialized metabolism. Microbiology 164, 946–955. [LINK]
(28) Mafu, S., Ding, Y., Murphy, K. M., Yaacoobi, O., Addison, J. B., Wang, Q., Shen, Z., Briggs, S. P., Bohlmann, J., Castro-Falcon, G., Hughes, C. C., Betsiashvili, M., Huffaker, A., Schmelz, E. A., and Zerbe, P. (2018) Discovery, biosynthesis and stress-related accumulation of dolabradiene-derived defenses in maize. Plant Physiol. 176, 2677–2690. [LINK]
(27) Gallagher, K. A., Wanger, G., Henderson, J., Llorente, M., Hughes, C. C., and Jensen, P. R. (2017) Ecological implications of hypoxia-triggered shifts in secondary metabolism. Environ. Microbiol. 19, 2182–2191. [LINK]
(26) Reimer, D., and Hughes, C. C.* (2017) Thiol-based probe for electrophilic natural products reveals that most of the ammosamides are artifacts. J. Nat. Prod. 80, 126–133. [LINK]
(25) Castro-Falcon, G., Hahn, D., Reimer, D., and Hughes, C. C.* (2016) Thiol probes to detect electrophilic natural products based on their mechanism of action. ACS Chem. Biol. 11, 2328–2336. [LINK]
(24) Richter, T. K. S., Hughes, C. C., and Moore, B. S. (2015) Sioxanthin, a novel glycosylated carotenoid, reveals an unusual subclustered biosynthetic pathway. Environ. Microbiol. 17, 2158–2171. [LINK]
(23) Alvarez-Mico, X., Jensen, P. R., Fenical, W., and Hughes, C. C.* (2013) Chlorizidine, a cytotoxic 5H-pyrrolo[2,1-a]isoindol-5-one-containing alkaloid from a marine Streptomyces sp. Org. Lett. 15, 988–991. [LINK]
(22) Yamanaka, K., Ryan, K. S., Gulder, T. A. M., Hughes, C. C., and Moore, B. S. (2012) Flavoenzyme-catalyzed atropo-selective N,C-bipyrrole homocoupling in marinopyrrole biosynthesis. J. Am. Chem. Soc. 134, 12434–12437. [LINK]
DOCTORATE AND POSTDOCTORATE
(21) Yang, M., Liu, Z., Hughes, C. C., Stern, A. M., Wang, H., Zhong, Z., Kan, B., Fenical, W., and Zhu, J. (2013) Bile salt-induced intermolecular disulfide bond formation activates Vibrio cholerae virulence. Proc. Natl. Acad. Sci. 110, 2348–2353.
(20) Haste, N. M., Hughes, C. C., Tran, D. N., Fenical, W., Jensen, P. R., Nizet, V., and Hensler, M. E. (2011) Pharmacological properties of the marine natural product marinopyrrole A against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 55, 3305–3312.
(19) Hughes, C. C., and Fenical, W. (2010) Antibacterials from the sea. Chem. - A Eur. J. 16, 12512–12525.
(18) Pangerl, M., Hughes, C. C., and Trauner, D. (2010) Total synthesis of newbouldine via reductive N–N bond formation. Tetrahedron 66, 6626–6631.
(17) Hughes, C. C., and Fenical, W. (2010) Total synthesis of the ammosamides. J. Am. Chem. Soc. 132, 2528–2529.
(16) Hughes, C. C., Kauffman, C. A., Jensen, P. R., and Fenical, W. (2010) Structures, reactivities, and antibiotic properties of the marinopyrroles A−F. J. Org. Chem. 75, 3240–3250.
(15) Hughes, C. C., Yang, Y. L., Liu, W. T., Dorrestein, P. C., La Clair, J. J., and Fenical, W. (2009) Marinopyrrole A target elucidation by acyl dye transfer. J. Am. Chem. Soc. 131, 12094–12096.
(14) Nett, M., Gulder, T. A. M., Kale, A. J., Hughes, C. C., and Moore, B. S. (2009) Function-oriented biosynthesis of β-lactone proteasome inhibitors in Salinispora tropica. J. Med. Chem. 52, 6163–6167.
(13) Hughes, C. C., MacMillan, J. B., Gaudêncio, S. P., Fenical, W., and La Clair, J. J. (2009) Ammosamides A and B target myosin. Angew. Chemie - Int. Ed. 48, 728–732.
(12) Hughes, C. C., MacMillan, J. B., Gaudêncio, S. P., Jensen, P. R., and Fenical, W. (2009) The ammosamides: structures of cell cycle modulators from a marine-derived Streptomyces species. Angew. Chemie - Int. Ed. 48, 725–727.
(11) Hughes, C. C., Prieto-Davo, A., Jensen, P. R., and Fenical, W. (2008) The marinopyrroles, antibiotics of an unprecedented structure class from a marine Streptomyces sp. Org. Lett. 10, 629–631.
(10) Miller, A. K., Hughes, C. C., Kennedy-Smith, J. J., Gradl, S. N., and Trauner, D. (2006) Total synthesis of (−)-heptemerone B and (−)-guanacastepene E. J. Am. Chem. Soc. 128, 17057–17062.
(9) Endicott, C. A., Strauss, H. L., Hughes, C. C., and Trauner, D. (2005) Infrared hole burning and conformational change in a borane-ammonia complex. J. Phys. Chem. A 109, 7714–7717.
(8) Bowie, A. L., Hughes, C. C., and Trauner, D. (2005) Concise synthesis of (±)-rhazinilam through direct coupling. Org. Lett. 7, 5207–5209.
(7) Hughes, C. C., Miller, A. K., and Trauner, D. (2005) An electrochemical approach to the guanacastepenes. Org. Lett. 7, 3425–8.
(6) Hughes, C. C., and Trauner, D. (2004) Palladium-catalyzed couplings to nucleophilic heteroarenes: The total synthesis of (−)-frondosin B. Tetrahedron 60, 9675–9686.
(5) Hughes, C. C., Kennedy-Smith, J. J., and Trauner, D. (2003) Synthetic studies toward the guanacastepenes. Org. Lett. 5, 4113–4115.
(4) Johnson, D. K.; Schillinger, K. J.; Kwait, D. M.; Hughes, C. C.; McNamara, E. J.; Ishmael, F.; O’Donnell, R. W.; Chang, M.-M.; Hogg, M. G.; Dordick, J. S.; Santhanam, L.; Ziegler, L. M.; Holland, J. A. (2002) Inhibition of NADPH oxidase activation in endothelial cells by ortho-methoxy-substituted catechols. Endothelium 9, 191–203.
(3) Hughes, C. C., Scharn, D., Mulzer, J., and Trauner, D. (2002) Borane-ammonia complexes stabilized by hydrogen bonding. Org. Lett. 4, 4109–11.
(2) Hughes, C. C., and Trauner, D. (2002) Concise total synthesis of (−)-frondosin B using a novel palladium-catalyzed cyclization. Angew. Chemie - Int. Ed. 41, 1569–1572.
(1) Hughes, C. C., and Trauner, D. (2002) The total synthesis of (−)-amathaspiramide F. Angew. Chemie - Int. Ed. 41, 4556–4559.
Hughes Research Group
Interfaculty Institute for Microbiology and Infection Medicine
University of Tübingen
Auf der Morgenstelle 28
72076 Tübingen Deutschland
Chambers C. Hughes, Ph.D.
phone: +49(0) 7071-2974623