Research Focus
Honors
Selected Publications
Contact
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Semmelhack?Lab?Website

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Faculty Assistant
Pattie Faranetta
pfaranetta@princeton.edu
Frick Laboratory, 228
609-258-5202



Research Focus
The theme of our research is the design, synthesis and evaluation of small molecules involved in biological processes. The projects proceed as a team effort, with close collaboration among chemists, biochemists and biologists.
A current area of emphasis is the phenomenon of “quorum sensing” in bacteria. Quorum sensing is a process of bacterial cell–cell communication that enables populations of cells to carry out behaviors in unison. It involves detection of the cell density-dependent accumulation of extracellular signal molecules called autoinducers that elicit population-wide changes in gene expression. In major human pathogens, such as Vibrio cholerae, Pseudomonas aeruginosa and Staphlococcus aureus, quorum sensing controls virulence. This raises the possibility that small molecules that influence quorum sensing could be used to control virulence and suggests a new approach for development of anti-infective drugs.
The structures of autoinducers are diverse as exemplified in the scheme below. Our group identified the key signals from V. cholerae [CAI-1 and En-CAI-1] and the multi-species autoinducer, AI-2, which has a novel boron-containing structure. Based on the native signals, we have identified analogs that are agonists and antagonists of the key receptor proteins for both V. choleraeand for P. aeruginosa. Related to this effort is the application of “chemical genetics” together with a genetics approach to map out the key features of the receptor protein in V. cholerae. Future targets for small molecule intervention include the enzymes responsible for the biosynthesis of the signals and other downstream proteins involved in the signaling cascades. The approaches include structure design based on the protein ligands/substrates, and also high-throughput screening of diverse chemical libraries to identify entirely novel structures with the appropriate activity.

We have collaborations focused on the novel cyclic-di-GMP signaling pathways in bacteria and have identified a set of novel structures with significant activity towards inhibiting the development of biofilms, a key virulence factor of P. aeruginosa. In a foray into neuroscience led by our colleagues in the Wang group, we reported the development of new techniques for the photo-release of neurotransmitters.


Research Areas
Catalysis / Synthesis
Chemical Biology



Honors
Arthur C. Cope Scholar Award, American Chemical Society (2014)
John Simon Guggenheim Fellow (1978 – 1979)
Camille and Henry Dreyfuss, Teacher-Scholar Grantee(1972 – 1977)
Alfred P. Sloan Foundation Fellow (1972 – 1975)


Selected Recent Publications
Shi, D. D.;Trigo, F. F.;Semmelhack, M. F.; Wang, S. S. H., "Synthesis and Biological Evaluation ofBis-CNB-GABA, aPhotoactivatableNeurotransmitter with Low Receptor Interference andChemical Two-PhotonUncagingProperties."Journal of the American Chemical Society2014,136(5), 1976-1981.
Perez, L. J.;Karagounis, T. K.; Hurley, A.;Bassler, B. L.;Semmelhack, M. F., "Highly potent, chemically stable quorum sensingagonistsforvibrioCholerae."Chemical Science2014,5(1), 151-155.
O'Loughlin, C. T.; Miller, L. C.;Siryaporn, A.;Drescher, K.;Semmelhack, M. F.;Bassler, B. L., "A quorum-sensing inhibitor blocksPseudomonasaeruginosavirulence andbiofilmformation."Proceedings of the National Academy of Sciences of the United States of America2013,110(44), 17981-17986.
Sambanthamoorthy, K.;Sloup, R. E.;Parashar, V.; Smith, J. M.; Kim, E. E.;Semmelhack, M. F.;Neiditch, M. B.; Waters, C. M., "Identification of Small Molecules That AntagonizeDiguanylateCyclaseEnzymes To InhibitBiofilmFormation."Antimicrobial Agents and Chemotherapy2012,56(10), 5202-5211.
Perez, L. J.; Ng, W.-L.;Marano, P.; Brook, K.;Bassler, B. L.;Semmelhack, M. F., "Role of theCAI-1Fatty Acid Tail in theVibriocholeraeQuorum Sensing Response."Journal of Medicinal Chemistry2012,55(22), 9669-9681.
Ng, W.-L.; Perez, L.; Cong, J.;Semmelhack, M. F.;Bassler, B. L., "Broad Spectrum Pro-Quorum-Sensing Molecules as Inhibitors of Virulence in Vibrios."PlosPathogens2012,8(6).
Marques, J. C.;Lamosa, P.; Russell, C.; Ventura, R.;Maycock, C.;Semmelhack, M. F.; Miller, S. T.; Xavier, K. B., "Processing the Interspecies Quorum-sensing SignalAutoinducer-2(AI-2) characterization of phospho-(S)-4,5-dihydroxy-2,3-pentanedioneisomerizationbyLsrGprotein."Journal of Biological Chemistry2011,286(20), 18331-18343.
Cowles, C. E.; Li, Y.;Semmelhack, M. F.;Cristea, I. M.;Silhavy, T. J., "The free and bound forms of Lpp occupy distinct subcellular locations in Escherichia coli."Molecular Microbiology2011,79(5), 1168-1181.
Ng, W.-L.; Perez, L. J.; Wei, Y.;Kraml, C.;Semmelhack, M. F.;Bassler, B. L., "Signal production and detection specificity inVibrioCqsA/CqsSquorum-sensing systems."Molecular Microbiology2011,79(6), 1407-1417.
Sambanthamoorthy, K.;Gokhale, A. A.; Lao, W.;Parashar, V.;Neiditch, M. B.;Semmelhack, M. F.; Lee, I.; Waters, C. M., "Identification of a NovelBenzimidazoleThat Inhibits BacterialBiofilmFormation in a Broad-Spectrum Manner."Antimicrobial Agents and Chemotherapy2011,55(9), 4369-4378.
Stanevich, V.;Jiang, L.;Satyshur, K. A.; Li, Y.; Jeffrey, P. D.; Li, Z.;Menden, P.;Semmelhack, M. F.;Xing, Y., "The Structural Basis for Tight Control ofPP2AMethylationand Function by LCMT-1."Molecular Cell2011,41(3), 331-342.
Bolitho,M. E.;Perez, L. J.; Koch, M. J.; Ng, W.-L.;Bassler, B. L.;Semmelhack, M. F., "Small molecule probes of the receptor binding site in theVibriocholeraeCAI-1quorum sensing circuit."Bioorganic& Medicinal Chemistry2011,19(22), 6906-6918.
Wei, Y.; Perez, L. J.; Ng,W.-L.;Semmelhack, M.F.;Bassler, B. L., "Mechanism ofVibriocholeraeAutoinducer-1Biosynthesis."Acs Chemical Biology2011,6(4), 356-365.
Ng, W.-L.; Wei, Y.; Perez, L. J.; Cong, J.; Long, T.; Koch, M.;Semmelhack, M. F.;Wingreen, N. S.;Bassler, B. L., "Probing bacterialtransmembranehistidinekinasereceptor-ligandinteractions with natural and synthetic molecules."Proceedings of the National Academy of Sciences of the United States of America2010,107(12), 5575-5580.
Kelly, R. C.;Bolitho, M. E.; Higgins, D. A.; Lu, W.; Ng, W.-L.; Jeffrey, P. D.;Rabinowitz, J. D.;Semmelhack, M. F.;Hughson, F. M.;Bassler, B. L., "TheVibriocholeraequorum-sensingautoinducerCAI-1: analysis of the biosynthetic enzyme CqsA."Nature Chemical Biology2009,5(12), 891-895.
Higgins, D. A.;Pomianek, M. E.;Kraml, C. M.; Taylor, R. K.;Semmelhack, M. F.;Bassler, B. L., "The majorVibriocholeraeautoinducerand its role in virulence factor production."Nature2007,450(7171), 883-886.
Rader, B. A.;Campagna, S. R.;Semmelhack, M. F.;Bassler, B. L.;Guillemin, K., "The quorum-sensing moleculeautoinducer2 regulates motility andflagellarmorphogenesisinHelicobacterpylori."Journal of Bacteriology2007,189(17), 6109-6117.
Pomianek, M. E.;Semmelhack, M. F., "Making bacteria behave: Newagonistsand antagonists of quorum sensing."Acs Chemical Biology2007,2(5), 293-295.
Xavier, K. B.; Miller, S. T.; Lu, W.; Kim, J.H.;Rabinowitz, J.;Pelczer, I.;Semmelhack, M. F.;Bassler, B. L., "Phosphorylationand processing of the quorum-sensing moleculeautoinducer-2in enteric bacteria."Acs Chemical Biology2007,2(2), 128-136.
Rickard, A. H.; Palmer, R. J.;Blehert, D. S.;Campagna, S. R.;Semmelhack, M. F.;Egland, P. G.;Bassler, B. L.;Kolenbrander, P. E., "Autoinducer2: a concentration-dependent signal formutualisticbacterialbiofilmgrowth."Molecular Microbiology2006,60(6), 1446-1456.
Semmelhack, M. F.;Hooley, R. J.;Kraml, C. M., "Synthesis ofplakortoneB and analogs."Organic Letters2006,8(23), 5203-5206.
Semmelhack, M. F.;Chlenov, A.; Ho, D. M., "Acceleratedareneligandexchange in the (arene)Cr(CO)(2)L series."Journal of the American Chemical Society2005,127(21), 7759-7773.
Semmelhack, M. F.;Campagna, S. R.;Federle, M. J.;Bassler, B. L., "An expeditious synthesis of DPD and boron binding studies."Organic Letters2005,7(4), 569-572.
Semmelhack, M. F.;Sarpong, R., "Kinetic analysis of a reactive model enediyne."Journal of Physical Organic Chemistry2004,17(9), 807-813.
Miller, S. T.; Xavier, K. B.;Campagna, S. R.;Taga, M. E.;Semmelhack, M. F.;Bassler, B. L.;Hughson, F. M., "Salmonellatyphimuriumrecognizes a chemically distinct form of the bacterial quorum-sensing signal Al-2."Molecular Cell2004,15(5), 677-687.