Summary

Our current research interests are in the area of antibiotic discovery for "neglected" diseases. Tuberculosis is a global human health problem of staggering proportions, causing 1.8 million deaths in 2016. Current TB drugs require up to nine months of treatment and poor compliance promotes the emergence of drug-resistant strains. We are using both structure-based and high-throughput screening approaches to discover improved RNAP inhibitors in collaboration with the VMCC here at U-M, the Franzblau lab at UIC and the Murakami lab at Penn State. Shigella flexneri is a human enteropathogen that infects ca. 165 million people and claims more than 1 million lives per year worldwide. Targeting Shigella virulence pathways is attractive because such drugs would be expected to exhibit less emergence of drug resistance and have no effect on normal colonic microbiota. We are using high-throughput screening to find molecules that block Shigella virulence without bacteriacidal activity.  Our current focus is the transcription factor VirF, which initiates expression of the key Shigella virulence genes.

Research Interests

  • Developing novel antibiotics targeting eubacterial and mycobacterial (for tuberculosis) RNA polymerase, in collaboration with the Showalter lab

  • Novel drug discovery against Shigella, one of the causative agents of acute diarrheal disease

  • Biosynthesis and physiological roles of the modified base queuine

Selected Publications

  • Ashkar, S.R., Rajeswaran, W., Lee, P.H., Thrasher, C.M., Franzblau, S.G., Murakami, K., Showalter, H.D.H., and Garcia, G.A., “Optimization of Benzoxazinorifamycins to Minimize hPXR Activation for Treatment of Tuberculosis and HIV Coinfection”, ACS Infectious Diseases (2022), https://doi.org/10.1021/acsinfecdis.1c00635, PMID:35772743.

     

  • Rajeswaran, W., Ashkar, S., Lee, P.H., Shin, Y., Franzblau, S.G., Murakami, K., Showalter, H.D.H., and Garcia, G.A., “Optimization of Benzoxazinorifamycins to Improve M. tuberculosis RNA Polymerase Inhibition and Treatment of Tuberculosis”, ACS Infectious Diseases, (2022), https://doi.org/10.1021/acsinfecdis.1c00636, PMID: 35772744.

     

  • Stefan, M.A., Velazquez, G.M., and Garcia, G.A., “High-throughput Screening to Discover Inhibitors of the CarD•RNA Polymerase Protein-Protein Interaction in Mycobacterium tuberculosis”, Nature Scientific Reports (2020), DOI: 10.1038/s41598-020-78269-3.  https://www.nature.com/articles/s41598-020-78269-3.epdf

     

  • Stefan, M.A., Ugur, F.S., and Garcia, G.A., "Source of the Fitness Defect in Rifamycin-Resistant M. Tuberculosis RNA Polymerase and the Mechanism of Compensation by Secondary Mutations”, Antimicrobial Agents and Chemotherapy (2018),62 (6), e00164-18, 1-13

     

  • Scharf, N.T., Kontos, A., Molodtsov, V., Murakami, K.S., and Garcia, G.A., “Novel Chemical Scaffolds for Inhibition of Rifamycin-Resistant RNA Polymerase Discovered from High-Throughput Screening”, SLAS Discovery (2017), 22 (3), 287-297, PMCID: PMC5323270.

     

  • Molodtsov, V., Scharf, N.T., Stefan, M.A., Garcia, G.A., and Murakami, K.S., “Structural Basis for Rifampin-Resistance of Bacterial RNA Polymerase by Clinically Important Rifampin Resistant Mutations”, Molecular Microbiology (2017), 103 (6), 1034-1045, PMCID: PMC5344776.

     

  • Emanuele, A.A. and Garcia, G.A., “Mechanism of Action and Initial, In vitro SAR of an Inhibitor of the Shigella flexneri Virulence Regulator VirF”, PLOS One (2015), e0137410 PMCID: PMC4564171.