Summary

A long-standing research interest of the Garcia lab has been the biosynthesis and physiological roles of modified bases in RNA. More recently we have shifted our focus to antibiotic discovery in two areas. Tuberculosis is a global human health problem of staggering proportions, causing nearly 1.4 million deaths in 2011. Current TB drugs require up to nine months of treatment and poor compliance promotes the emergence of drug-resistant strains. We are using a structure-based approach to discover improved RNAP inhibitors in collaboration with the Showalter lab here at U-M 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 have successfully conducted high-throughput screens of ~142,000 compounds and ~20,000 natural product extracts against VirF, which initiates expression of the key Shigella virulence genes. We are characterizing the hits which block VirF activity in collaboration with the Sherman lab here at U-M and the Maurelli lab at USUHS in Maryland.

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

  • 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 (2016), DOI:10.1177/1087057116679994.

  • 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 (2016) DOI: 10.1111/mmi.13606.

  • 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.

  • *Emanuele, A.A., Praskievicz, N.A., Chen, Y.-C., Maurelli, A.T., and Garcia, G.A., “Potential Novel Antibiotics from HTS Targeting the Virulence-regulating Transcription Factor, VirF, from Shigella flexneri”, Journal of Antibiotics (2014), 67, 379-386, PMCID: 4050983. *Note that this paper was featured on the journals webpage for this issue and was noted as #1 of the top 10 articles downloaded in the 15 days since the issue was published.

  • †Molodtsov, V., Nawarathne, I.N., Scharf, N.T., Kirchhoff, P.D., Showalter, H.D.H., Garcia, G.A., and Murakami, K.S. “X-ray Crystal Structures of the Escherichia coli RNA Polymerase in Complex with Benzoxazinorifamycins” Journal of Medicinal Chemistry (2013), 56 (11), 4758-4763 * This paper was highlighted on the cover of this issue. *Molodtsov, V., Nawarathne, I.N., Scharf, N.T., Kirchhoff, P.D., Showalter, H.D.H., Garcia, G.A., and Murakami, K.S. “X-ray Crystal Structures of the Escherichia coli RNA Polymerase in Complex with Benzoxazinorifamycins” Journal of Medicinal Chemistry (2013), 56 (11), 4758-4763, PMCID: 3745299. † This paper was highlighted on the cover of this issue.