Hughes
Research
group
NATURAL PRODUCTS
University of Tuebingen
Auf der Morgenstelle 28
72076 Tuebingen, Germany
RESEARCH
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
Labeled NPs
ACS Chem. Biol. 2016, 11, 2328–2336.
J. Nat. Prod. 2017, 80, 126–133.
J. Med. Chem. 2018, 61, 10463–10472.
Target: epoxides, α,β-unsaturated carbonyl groups, β-lactones, β-lactams
The nitrosopyridine probe
Labeled NPs
Target: conjugated alkenes
The azide probe
Labeled NPs
Target: terminal alkynes
The tetrazine probe
COMING SOON!
Target: isocyanides
The diazo probe
COMING SOON!
Target: phosphonates
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.
EDUCATION
1997–1999 Geneseo College (SUNY)
Research assistant
1999–2004 UC Berkeley
Graduate student
RESEARCH EXPERIENCE
2005–2012 Scripps Institution of Oceanography, UC San Diego
Postdoctoral scholar/Research associate IV
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
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group
Smith Babiaka, postdoctoral scholar
B.S., University of Buea, Cameroon
M.S., University of Buea, Cameroon
Ph.D., University of Buea, Cameroon
Shu-Ning Xia, Ph.D. student
B.E., Qilu University of Technology
M.E., Zhejiang University of Technology
publications
(42) Wilkinson IVL, Castro‐Falcón G, Roda‐Serrat MC, Purdy TN, Straetener J, Brauny MM, Maier L, Brötz‐Oesterhelt H, Christensen LP, Sieber SA,* Hughes CC.* The cyanobacterial “nutraceutical” phycocyanobilin inhibits cysteine protease legumain. ChemBioChem. 2023;e202200455:1-10. doi:10.1002/cbic.202200455
(41) Zhang L, Esquembre LA, Xia SN, Oesterhelt F, Hughes CC,* Brötz-Oesterhelt H,* Teufel R.* Antibacterial synnepyrroles from human-associated Nocardiopsis sp. show protonophore activity and disrupt the bacterial cytoplasmic membrane. ACS Chem Biol. 2022;17:2836-2848. doi:10.1021/acschembio.2c00460
(40) Reher R, Aron AT, Fajtová P, Stincone P, Wagner B, Pérez-Lorente AI, Liu C, Shalom IYB, Bittremieux W, Wang M, Jeong K, Matos-Hernandez ML, Alexander KL, Caro-Diaz EJ, Naman CB, Scanlan JHW, Hochban PMM, Diederich WE, Molina-Santiago C, Romero D, Selim KA, Sass P, Brötz-Oesterhelt H, Hughes CC, Dorrestein PC, O’Donoghue AJ, Gerwick WH, Petras D. Native metabolomics identifies the rivulariapeptolide family of protease inhibitors. Nat Commun. 2022;13:1-12. doi:10.1038/s41467-022-32016-6
(39) Engelbrecht A, Wolf F, Esch A, Kulik A, Kozhushkov SI, de Meijere A, Hughes CC,* Kaysser L.* Discovery of a cryptic nitro intermediate in the biosynthesis of the 3-(trans-2′-aminocyclopropyl)alanine moiety of belactosin A. Org Lett. 2022;24:736-740. doi:10.1021/acs.orglett.1c04205
(38) Hughes CC. Chemical labeling strategies for small molecule natural product detection and isolation. Nat Prod Rep. 2021;38:1684-1705. doi:10.1039/d0np00034e
ASSISTANT PROFESSOR (SCRIPPS INSTITUTION OF OCEANOGRAPHY)
(37) Förster C, Handrick V, Ding Y, Nakamura Y, Paetz C, Schneider B, Castro-Falcón G, Hughes CC, Luck K, Poosapati S, Kunert G, Huffaker A, Gershenzon J, Schmelz EA, Köllner TG. Biosynthesis and antifungal activity of fungus-induced O-methylated flavonoids in maize. Plant Physiol. 2022;188:167-190. doi:10.1093/plphys/kiab496
(36) Tuttle RN, Rouse GW, Castro-Falcón G, Hughes CC, Jensen PR. Specialized metabolite-mediated predation defense in the marine actinobacterium Salinispora. Appl Environ Microbiol. 2022;88:e01176-21. doi:10.1128/AEM.01176-21
(35) Ding Y, Murphy KM, Poretsky E, Mafu S, Yang B, Char SN, Christensen SA, Saldivar E, Wu M, Wang Q, Ji L, Schmitz RJ, Kremling KA, Buckler ES, Shen Z, Briggs SP, Bohlmann J, Sher A, Castro-Falcon G, Hughes CC, Huffaker A, Zerbe P, Schmelz EA. Multiple genes recruited from hormone pathways partition maize diterpenoid defences. Nat Plants. 2019;5:1043-1056. doi:10.1038/s41477-019-0509-6
(34) Seiler GS, Hughes CC. Progress toward the total synthesis of lymphostins: Preparation of a functionalized tetrahydropyrrolo[4,3,2-de]quinoline and unusual oxidative dimerization. J Org Chem. 2019;84:9339-9343. doi:10.1021/acs.joc.9b01041
(33) Moss NA, Seiler G, Leao TF, Castro-Falcon G, Gerwick L, Hughes CC, Gerwick WH. Nature’s combinatorial biosynthesis produces vatiamides A–F. Angew Chem Int Ed. 2019;58:9027-9031. doi:10.1002/anie.201902571
(32) Kearney SE, Zahoránszky-Kohalmi G, Brimacombe KR, Henderson MJ, Lynch C, Zhao T, Wan KK, Itkin Z, Rohde JM, et al. Canvass: A crowd-sourced, natural-product screening library for exploring biological space. ACS Cent Sci. 2018;4:1727-1741. doi:10.1021/acscentsci.8b00747
(31) Castro-Falcón G, Seiler G, Demir O, Rathinaswamy M, Hamelin D, Hoffmann RM, Makowski S, Letzel AC, Field S, Burke J, Amaro RE, Hughes CC. 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. 2018;61:10463-10472. doi:10.1021/acs.jmedchem.8b00975
(30) Castro-Falcón G, Millán-Aguiñaga N, Roullier C, Jensen PR, Hughes CC. Nitrosopyridine probe to detect polyketide natural products with conjugated alkenes: Discovery of novodaryamide and nocarditriene. ACS Chem Biol. 2018;13:3097-3106. doi:10.1021/acschembio.8b00598
(29) Patin N V, Floros DJ, Hughes CC, Dorrestein PC, Jensen PR. The role of inter-species interactions in Salinispora specialized metabolism. Microbiology. 2018;164:946-955. doi:10.1099/mic.0.000679
(28) Mafu S, Ding Y, Murphy KM, Yaacoobi O, Addison JB, Wang Q, Shen Z, Briggs SP, Bohlmann J, Castro-Falcon G, Hughes CC, Betsiashvili M, Huffaker A, Schmelz EA, Zerbe P. Discovery, biosynthesis and stress-related accumulation of dolabradiene-derived defenses in maize. Plant Physiol. 2018;176(4):2677-2690. doi:10.1104/pp.17.01351
(27) Gallagher KA, Wanger G, Henderson J, Llorente M, Hughes CC, Jensen PR. Ecological implications of hypoxia-triggered shifts in secondary metabolism. Environ Microbiol. 2017;19:2182-2191. doi:10.1111/1462-2920.13700
(26) Reimer D, Hughes CC. Thiol-based probe for electrophilic natural products reveals that most of the ammosamides are artifacts. J Nat Prod. 2017;80:126-133. doi:10.1021/acs.jnatprod.6b00773
(25) Castro-Falcon G, Hahn D, Reimer D, Hughes CC. Thiol probes to detect electrophilic natural products based on their mechanism of action. ACS Chem Biol. 2016;11:2328-2336. doi:10.1021/acschembio.5b00924
(24) Richter TKS, Hughes CC, Moore BS. Sioxanthin, a novel glycosylated carotenoid, reveals an unusual subclustered biosynthetic pathway. Environ Microbiol. 2015;17(6):2158-2171. doi:10.1111/1462-2920.12669
(23) Álvarez-Micõ X, Jensen PR, Fenical W, Hughes CC. Chlorizidine, a cytotoxic 5H-pyrrolo[2,1-a]isoindol-5-one-containing alkaloid from a marine Streptomyces sp. Org Lett. 2013;15:988-991. doi:10.1021/ol303374e
(22) Yamanaka K, Ryan KS, Gulder TAM, Hughes CC, Moore BS. Flavoenzyme-catalyzed atropo-selective N,C-bipyrrole homocoupling in marinopyrrole biosynthesis. J Am Chem Soc. 2012;134(30):12434-12437. doi:10.1021/ja305670f
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.
CONTACT
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.
email: chambers.hughes@uni-tuebingen.de
phone: +49(0) 7071-2976989
Ph.D. positions available
send via email:
CV, motivation letter, references, transcripts
