Project Details
Description
Preliminary work establishes that three natural products-the polyketide-derived a-pyrone myxopyronin, the
Dolyketide-derived a-pyrone corallopyronin, and the polyketide-derived macrocylic lactone ripostatin-inhibit
Dacterial RNA polymerase (RNAP) through interactions with the RNAP "switch region," a structural element
that mediates conformational changes required for RNAP to bind and retain the DMAtemplate in
transcription. The compounds do not inhibit eukaryotic RNAP I, RNAP II, or RNAP III. The compounds
ootently inhibit Gram-positive and Gram-negative bacterial growth, exhibit no cross-resistance with the
nhibitors of bacterial RNAP in current clinical use in therapy of bacterial infection (therifamycin antibacterial
agents, rifampicin, rifapentine, and rifabutin), and exhibit no cross-resistance with other inhibitors of bacterial
RNAP under evaluation for future clinical use in therapy of bacterial infection.
The proposed work wilt use x-ray crystallography, ensemble and single-molecule fluorescence resonance
energy transfer, single-molecule nanomanipulation, molecular cloning, surrogate-host expression,
structure-based screening, and de novo screening, to address four specific aims:
Specific Aim 1: Determination of structures of complexes of RNAP with switch-region-target inhibitors
Specific Aim 2: Determination of mechanisms of inhibition of RNAP by switch-region-target inhibitors
Specific Aim 3: Cloning, characterization, and surrogate-host expression of biosynthetic gene clusters
for switch-region-target inhibitors
Specific Aim 4: Identification and characterization of novel switch-region-target inhibitors
The results will enable development of new broad-spectrum antibacterial agents that will be effective against
bacterial strains resistant to currently used antibacterial agents. As such, the results will have direct
relevance to public health and to development of countermeasures against bacterial strains that could be
used in biowarfare or bioterrorism. In addition, the results will contribute to understanding RNAP structure
and function and will provide tools for analysis of RNAP structure and function.
Status | Finished |
---|---|
Effective start/end date | 1/1/07 → 12/31/12 |
Funding
- National Institute of Allergy and Infectious Diseases: $588,112.00
- National Institute of Allergy and Infectious Diseases: $588,112.00
- National Institute of Allergy and Infectious Diseases: $598,532.00
- National Institute of Allergy and Infectious Diseases: $582,230.00
- National Institute of Allergy and Infectious Diseases: $559,639.00
ASJC
- Infectious Diseases
- Genetics
- Molecular Biology
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