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. cholerae and 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.
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)
Shi, D. D.; Trigo, F. F.; Semmelhack, M. F.; Wang, S. S. H., "Synthesis and Biological Evaluation of Bis-CNB-GABA, a Photoactivatable Neurotransmitter with Low Receptor Interference and Chemical Two-Photon Uncaging Properties." Journal of the American Chemical Society 2014, 136 (5), 1976-1981.
Perez, L. J.; Karagounis, T. K.; Hurley, A.; Bassler, B. L.; Semmelhack, M. F., "Highly potent, chemically stable quorum sensing agonists for vibrio Cholerae." Chemical Science 2014, 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 blocks Pseudomonas aeruginosa virulence and biofilm formation." Proceedings of the National Academy of Sciences of the United States of America 2013, 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 Antagonize Diguanylate Cyclase Enzymes To Inhibit Biofilm Formation." Antimicrobial Agents and Chemotherapy 2012, 56 (10), 5202-5211.
Perez, L. J.; Ng, W.-L.; Marano, P.; Brook, K.; Bassler, B. L.; Semmelhack, M. F., "Role of the CAI-1 Fatty Acid Tail in the Vibrio cholerae Quorum Sensing Response." Journal of Medicinal Chemistry 2012, 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." Plos Pathogens 2012, 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 Signal Autoinducer-2 (AI-2) characterization of phospho-(S)-4, 5-dihydroxy-2, 3-pentanedione isomerization by LsrG protein." Journal of Biological Chemistry 2011, 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 Microbiology 2011, 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 in Vibrio CqsA/CqsS quorum-sensing systems." Molecular Microbiology 2011, 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 Novel Benzimidazole That Inhibits Bacterial Biofilm Formation in a Broad-Spectrum Manner." Antimicrobial Agents and Chemotherapy 2011, 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 of PP2A Methylation and Function by LCMT-1." Molecular Cell 2011, 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 the Vibrio cholerae CAI-1 quorum sensing circuit." Bioorganic & Medicinal Chemistry 2011, 19 (22), 6906-6918.
Wei, Y.; Perez, L. J.; Ng, W.-L.; Semmelhack, M. F.; Bassler, B. L., "Mechanism of Vibrio cholerae Autoinducer-1 Biosynthesis." Acs Chemical Biology 2011, 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 bacterial transmembrane histidine kinase receptor-ligand interactions with natural and synthetic molecules." Proceedings of the National Academy of Sciences of the United States of America 2010, 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., "The Vibrio cholerae quorum-sensing autoinducer CAI-1: analysis of the biosynthetic enzyme CqsA." Nature Chemical Biology 2009, 5 (12), 891-895.
Higgins, D. A.; Pomianek, M. E.; Kraml, C. M.; Taylor, R. K.; Semmelhack, M. F.; Bassler, B. L., "The major Vibrio cholerae autoinducer and its role in virulence factor production." Nature 2007, 450 (7171), 883-886.
Rader, B. A.; Campagna, S. R.; Semmelhack, M. F.; Bassler, B. L.; Guillemin, K., "The quorum-sensing molecule autoinducer 2 regulates motility and flagellar morphogenesis in Helicobacter pylori." Journal of Bacteriology 2007, 189 (17), 6109-6117.
Pomianek, M. E.; Semmelhack, M. F., "Making bacteria behave: New agonists and antagonists of quorum sensing." Acs Chemical Biology 2007, 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., "Phosphorylation and processing of the quorum-sensing molecule autoinducer-2 in enteric bacteria." Acs Chemical Biology 2007, 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., "Autoinducer 2: a concentration-dependent signal for mutualistic bacterial biofilm growth." Molecular Microbiology 2006, 60 (6), 1446-1456.
Semmelhack, M. F.; Hooley, R. J.; Kraml, C. M., "Synthesis of plakortone B and analogs." Organic Letters 2006, 8 (23), 5203-5206.
Semmelhack, M. F.; Chlenov, A.; Ho, D. M., "Accelerated arene ligand exchange in the (arene)Cr(CO)(2)L series." Journal of the American Chemical Society 2005, 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 Letters 2005, 7 (4), 569-572.
Semmelhack, M. F.; Sarpong, R., "Kinetic analysis of a reactive model enediyne." Journal of Physical Organic Chemistry 2004, 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., "Salmonella typhimurium recognizes a chemically distinct form of the bacterial quorum-sensing signal Al-2." Molecular Cell 2004, 15 (5), 677-687.