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Current Trainees

 

Jacob Choby - Mentor:  Eric Skaar (Pathology, Microbiology, Immunology)

“Mechanistic studies of a  small molecule inhibitor of fermenting S. aureus

Research Description: 
Staphylococcus aureus is a Gram positive pathogen responsible for extensive morbidity and mortality worldwide. During infection, oxygen levels drop creating a hypoxic or anaerobic local environment. In the absence of oxygen, S. aureus will produce energy by fermentation instead of aerobic respiration. The metabolic switch to fermentation also produces the clinically relevant small colony variant phenotype which is recalcitrant to antibiotic treatment and may be the etiological agent of persistent infections. Previous work in the laboratory has shown that a small molecule from a high through screen of the VICB compound library (‘8882) which stimulates endogenous heme biosynthesis, also diminishes fermentative activity and is bacteriostatic to fermenting S. aureus. We are working to understand the mechanism of ‘8882 toxicity by screening for mutants that are resistant and investigating the metabolic state of ‘8882 treated S. aureus.

Awards:
CBI Training Grant

Conference Presentations:

  • Poster: S. aureus SaeRS facilitates toxicity of a small molecule inhibitor of fermentation. Vanderbilt Institute for Chemical Biology Annual Symposium, August 2014
  • Poster: S. aureus SaeRS facilitates toxicity of a small molecule inhibitor of fermentation. International Conference on Gram-positive Pathogens, University of Nebraska Medical Center, October 12-15, 2014
  • Poster: A small molecule inhibitor is toxic to S. aureusin an Sae-dependent manner, Vanderbilt Symposium on Infection and Immunity, April 10, 2015
  • Poster: A small molecule inhibitor is toxic to S. aureusin an Sae-dependent manner, Wind River Conference on Prokaryotic Biology, June 10-14, 2015
  • Poster: Regulation of HemA, the initial enzyme in Staphylococcus aureus heme biosynthesis  Vanderbilt Institute for Chemical Biology Annual Symposium, August  2015
     
 

Kelly Craft - Mentor:  Steve Townsend (Chemistry)

“Synthesis and Biological Evaluation of Lacto-N-tetraose and Congeners”

Research Description:
Human milk oligosaccharides (HMOs) are a class of complex glycans unique to human breast milk. These carbohydrates offer the infant a wide variety of health benefits including infection prevention and healthy gut development. It is important to note most biological benefits afforded by HMOs are structurally specific. As it is difficult to obtain homogenous HMOs from breast milk in quantities sufficient to recreate their concentration in milk, there is currently an unmet need determining specific HMO structure-activity relationships. To address this need, we first propose to develop chemoenzymatic syntheses which will allow access to an assortment of HMOs in multigram quantities. Next, we propose to determine the ability of these compounds to foster the development of a healthy gut through evaluation of their bifidogenicity.

Awards:
VICB Fellowship
CBI Training Grant

Conference Presentations:
CBI Career Conference flash talk (2015)

     
 

Alexander Geanes - Mentors:  Jens Meiler (Chemistry) & Craig Lindsley, (Neuroscience/Drug Discovery)

“Development and application of ligand-based computer aided drug design algorithms”

Research Description:
De-novo drug design is a technique by which computational algorithms can be used to design therapeutic candidates or biological probes that have a high probability of biological activity. My project focuses on the development and application of de-novo drug design algorithms that leverage machine-learning based quantitative structure activity relationship (QSAR) models to direct their design routines, and applying these algorithms to medicinal chemistry projects to discover novel biologically active compounds. The main biological target of interest to this project is muscarinic acetylcholine receptor M5. The ultimate goal for this target is to develop M5-selective negative allosteric modulators (NAMs) or orthosteric antagonists with favorable physicochemical properties that can be used in proof-of-concept studies for determining the role M5 plays in addiction and reward pathways in rats. In addition, I am participating in a collaboration with the Hamm lab to discover novel antagonists of the protease activated receptor 4 (PAR4), a factor that has been association with blood clotting.

Grants:
2014 ACS CINF Scholarship for Scientific Excellence (Applied)
2014 NSF Graduate Research Fellowship (Awarded)

Conference Presentations:
American Chemical Society Southeast Regional Meeting, 2014 (Poster/Abstract)
American Chemical Society 248th National Meeting, 2014 (Poster/Abstract)
Vanderbilt Institute of Chemical Biology Symposium, 2014 (Poster/Abstract)
Vanderbilt Institute of Chemical Biology Symposium, 2015 (Poster/Abstract)
CBI Career Development Conference, August 2015 (Poster)

     
 

John Hayes - Mentor:  Steve Townsend (Chemistry)

"Chemical Synthesis and Biological Evaluation of Lacto-N-neotetraose and Related Congeners"

Research Description:
The benefits of breastfeeding have become widely known and it is also known that many of those benefits involving the development of the infant gut are attributed to human milk oligosaccharides (HMO).  HMOs are recognized uniquely for their ability to stimulate growth in bifidobacteria and deter infection caused by harmful bacteria.  In order to better understand these properties, my project first aims to synthesize the human milk tetrasaccharide lacto-N-neotetraose.  The production of this compound will be performed in a manner that will provide facile access to a small pool of pentasaccharides.  Following the synthesis of the target molecules, biological testing will be performed to determine the role that the oligosaccharides play in inhibition of pathogenic adhesion.

Grants:
NIH F31 Individual NRSA for Diversity PhD Students ( Applied)

Conference Presentations:
Fall 2014 – Progress Towards the Synthesis of Lacto-N-neotetraose, VICB Symposium, poster presentation.

     
 

Jason Hudlicky - Mentor:  Gary Sulikowski (Chemistry)

“Total Synthesis of Bielschowskysin”

Research Description:

Progress towards the total synthesis of bielschowskysin, a marine natural product with moderate anti-malarial and anti-proliferative activity. Upon completion of the synthesis, further biological evaluations will be completed.

Grants:
NSERC Doctoral Fellowship (Applied)
NSF Graduate Research Fellowship (Applied)

Conference Presentations:
Flash talk at CBI Career Development Conference

     
 

Reece Knippel - Mentor:  Eric Skaar (Pathology, Microbiology, Immunology)

“The role of heme in Clostridium difficile pathogenicity ”

Research Description:

Clostridium difficile is a Gram-positive, spore-forming anaerobic bacterium that infects the colon, causing a range of symptoms from infectious diarrhea to death. In the United States between 2000 and 2005, the number of C. difficile-related infections rose by 23% per year in addition to quadrupling mortality rates. However, little is known about the pathogenesis of C. difficile’s interaction with the host and more specifically the aspects of inflammatory response to infection has not been fully characterized. We hypothesize that C. difficile’s ability to acquire and metabolize heme from the host constitutes a critical role in the severity of infection. Understanding these mechanisms could lead to novel therapeutic strategies to combat this dire threat to public health. 

Awards:
Chemical Biology Interface Research Supplement

     
 

Evan Perry - Mentor:  Stephen Fesik, Biochemistry)

“Small Molecule Inhibitors of Immune Checkpoint Proteins”

Research Description:
CTLA-4 and PD-L1 are checkpoint proteins that suppress the activity of the immune response against cancer. Recent clinical data with antibody based therapeutics have shown great success in blocking these checkpoints to stimulate the immune system to fight cancer. To date no small molecules have been tested in clinical trails against these highly validated targets. My research is focused on using both fragment and structure based methods to develop small molecule inhibitors against the checkpoint pathways of CTLA-4 and PD-L1.

Honors, Awards, Fellowships, Workshops:
Chemistry-Biology Interface Career Development

Conference Presentations:
Poster Presentation at CBI Career Development Conference (2015)

     
 

James Poland - Mentor:  John McLean (Chemistry)

“Utilizing Untargeted Ion Mobility- Mass Spectrometry Methodology to Answer Biological Questions”

Research Description:
Mass spectrometry based metabolomics seeks to identify the inventory of small molecules (i.e., <1600 Da) that are the by-products of, or directly involved in, biological processes. Due to the chemical diversity represented by endogenous metabolites, comprehensive molecular analysis is difficult for human-based studies. I utilize multidimensional chemical analysis based on liquid chromatography coupled to ion mobility-mass spectrometry (LC-IM-MS) in order to increase the detection and characterization of small molecule. A rapid, multi-tier validation workflow is used to identify metabolites of interest. Descriptors such as retention time (RT), drift time (DT), mass-to-charge ratio (m/z), and tandem MS/MS spectra are used to increase the confidence of the identification. Pathway analysis software is then be used to find the biological root for changes in the metabolome.

Workshops:
Waters Sample Preparation Workshop
Mass Spectrometry Metabolomic Workshop

Conference Presentations:

  • James C. Poland, “Metabolomic Analysis of Lung Epithelial Cells using Ion Mobility-Mass Spectrometry” 3rd Annual Bridge Research Celebration Day, Nashville TN. (August 2015) Oral
  • James C. Poland, M. Ray Keller, Stacy D. Sherrod, John A. Mclean. “Metabolomic Analysis of Lung Epithelial Cells using Ion Mobility-Mass Spectrometry” 2015 VICB Student Research Symposium, Nashville TN. (August 2015) Poster
  • James C. Poland, M. Ray Keller, Stacy D. Sherrod, John A. Mclean. “Metabolomic Analysis of Lung Epithelial Cells using Ion Mobility-Mass Spectrometry” 2015 Chemistry-Biology Interface Career Development Conference, Nashville TN. (August 2015) Poster
  • James C. Poland, M. Ray Keller, Stacy D. Sherrod, John A. Mclean. “Metabolomic Analysis of Lung Epithelial Cells using Ion Mobility-Mass Spectrometry” 63rd American Society for Mass Spectrometry Conference on Mass Spectrometry and Applied Topics, St. Louis MO (May 2015). Poster
     
 

Francis Prael - Mentor:  Dave Weaver (Pharmacology)

“Validation of Novel Insecticidal Targets for the Management of Vector Borne Disease”

Research Description:
Vector-borne diseases infect hundreds of millions of people each year. In addition to claiming over a million lives annually, these diseases are a tremendous physical and economic burden to those afflicted with them. Insecticides constitute one of the most effective means we have to manage these illnesses and have been integral to the decline in disease incidence seen in recent years. However, increasing insecticide resistance is threatening to undo this progress. The discovery and development of novel insecticides to combat insecticide resistance is therefore essential for continued success in controlling vector-borne disease. Kcc is a potassium/chloride cotransporter whose dysfunction is strongly linked to seizures and death in insects, thereby making it an attractive insecticidal target. We are using high-throughput screening, together with collaborations with insect toxicologists and chemists, to discover chemical probes against Kcc. We will use these probes to evaluate the potential of Kcc as a novel target for insecticides. Through our work, we aim to lay the foundation for the development of a new class of insecticide for managing these terrible diseases.

Grants:
CBI Training Grant
CBI Research Supplement

     
 

Audrey Ynigez-Gutierrez - Mentor:  Brian Bachmann (Chemistry)

“Investigations into the Biosynthesis and Mechanism of Action of the Everninomicins”

Research Description:
Everninomicins are complex polysaccharides produced by Micromonospora carbonacea that contain a number of unique structural features such as orthoester linkages, a methylenedioxy bridge, a nitro sugar, and a dichloroisoeverninic acid moiety. The biosynthetic mechanism of everninomicins is not completely understood and its unique mechanism of action is not clear. Therefore, we propose to revitalize the everninomicins. We intend to use genetic deletions and chemical complementation studies to investigate the biosynthesis of some of the most unique components of everninomicin. We plan to take advantage of our increasing understanding of the bacterial machinery to develop analogs of everninomicin using emerging genetic manipulation techniques and purified proteins. Everninomicin analogs will be evaluated for their ability to inhibit bacterial protein translation and enhanced antimicrobial properties.

Fellowships:
Vanderbilt Institute for Chemical Biology (VICB) Fellowship in Chemical Biology: August 2014 – June 2015

Grants:
2016 NSF Graduate Research Fellowship Program, “Investigations into the Biosynthesis and Mechanism of Action of the Everninomicins” (Applied)

     
     
     
     
     
     

 

 

 

 

 

 




 

 

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