2017 Trainees
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Minu Bidzimou
Mentor: Gary Sulikowski
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Lee Cantrell Home Institution: Whitworth University Research Abstract: Inuloxin A is a phytotoxin obtained from Inula viscosa, a widespread Mediterranean plant well known for its therapeutic metabolites. Specifically, Inuloxin A displays inhibition towards Leishmania donovani: a parasite responsible for visceral leishmaniasis. The absolute configuration (AC) of chiral molecules like Inuloxin A is critical to their bioactivities. Therefore, we used chiroptical spectroscopic measurements and predictions to assign the absolute configuration of Inuloxin A. Using Gaussian09 programs, we optimized the geometry of various enantiomeric conformers of Inuloxin A and then isolated the lowest energy conformers for each enantiomer. After applying a Boltzmann distribution, we interpreted the theoretical spectra against experimental spectrum by visual and quantitative analysis in CDSpecTech programs. No chiroptical spectra could facilitate definitive AC assignment; however, the AC (7R,8R,10S) is suggested. |
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Amanda Cao
Mentor: Lauren Buchanan
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Gabriel D'Agistino
Mentor: Brian Bachmann
Myxobacteria is one such underexplored genus. With over 40 new products discovered in the last 8 years and some entering clinical trials for therapeutic use, they serve as a potential reservoir for new products. We use the model myxobacterium Myxococcus xanthus DK1622. DK1622 encodes 23 biosynthetic gene clusters but only 13 have known products. Previous studies in non-myxobacteria found that sub-lethal antibiotics or rare earth metals stimulate natural product synthesis. Here, we address how these stimuli affect natural product production in DK1622. We isolate natural products in the presence and absence of putative stimuli using liquid chromatography-mass spectrometry (LC-MS) and comparative metabolomics methodologies. The study serves as a basis for understanding how stimuli affect natural product production in mxyobacteria. |
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Lauren Harris
Mentor: Sandra Rosenthal
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Hyungyu Lee
Mentor: Jeffrey Johnston
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Emily Lilla Home Institution: Michigan Technological University Research Abstract: Cardiac disease is the leading cause of death in the United States, and the current methods of treatment on the market are known to cause excess and sometimes fatal bleeding, such as Warfarin and Plavix. The Protease-Activated Receptors subtype 1 and 4, located on platelets, are responsible for the activation of clotting, the body’s response to excess bleeding. Targeting Protease-Activated Receptor-4 (PAR4) exclusively could allow for clotting while preventing thrombosis, or the formation of a blood clot. Because the protein crystal structure is not available, we use a homology modeling method in order to transition from a competitive molecular series to a noncompetitive molecular series. We intend to develop a series of molecules that have improved target binding to the PAR4 while maintaining potency and pharmacokinetic properties. We aim to use the homology model to drive structure activity relationship (SAR) with various organic chemistry methods, in order to develop a noncompetitive antagonist for PAR4. In developing this anti-platelet series of molecules the hope is that patients will no longer have to struggle with the negative side effects of the current therapeutics. |
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Claire Mammoser
Mentor: David Wright
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Edgar Marroquin
Mentor: Michael Stone
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Audrey Thomas
Mentor: Eric Skaar and Borden Lacy
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Erin Uhleski Home Institution: Michigan State University Research Abstract: Healthcare-associated infections cause significant morbidity and mortality in the United States. The bacteria Staphylococcus aureus and Acinetobacter baumannii are both considered serious threats by the CDC due to multi-drug resistance, making any infection they cause difficult to remedy. These pathogens often infect immunosuppressed hospital patients which can result in pneumonia or bloodstream infections. Subsequently, it is vital that these organisms are studied to discover alternative treatments for resistant infections. By structurally analyzing proteins from these bacteria that may have a role in survival mechanisms, it is possible to establish important regions for protein function. To select our protein targets, we used multiple bioinformatic tools to analyze protein characteristics that could influence expression and crystallization. Initial recombinant protein expression trials identified two promising candidates for crystallization, HemA from S. aureus and HutC from A. baumannii. We have mutated several residues near the N-terminus of HemA, an enzyme involved in the heme biosynthesis pathway, to improve its stability. Additionally, we have optimized expression and purification of the transcriptional regulator HutC. Examining these two proteins in broad crystallization screens will reveal favorable conditions for crystal formation. Ultimately the information gathered from these structures will inform functional studies that may uncover downstream effects that these proteins have within the cell. Such knowledge could give us a better understanding of their function and may reveal new targets for the next generation of antimicrobials. |
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