Tuberculosis (TB) kills more young and middle-aged adults worldwide than any other disease with the exception of AIDS. Furthermore, TB is the leading cause of morbidity and mortality among the population living with HIV/AIDS. While TB is generally perceived as a disease afflicting the poorest countries, the rapid increase in cases of multidrug-resistant tuberculosis (MDR-TB) and its spread to industrialized nations makes the disease a global threat. As primary drugs are rendered ineffective, second-line agents that are more expensive, usually less effective and often more toxic must be used. Hence, the need for new anti-TB drugs has never been greater, yet it has been over 30 years since the introduction of the last novel antitubercular agent. Advances to improve potency, decrease toxicity, and shorten the duration of therapy would have an enormous impact on world health and healthcare costs. This application describes an approach to access, utilize and manipulate peptide biosynthesis genes that direct precursor construction and post-assembly tailoring to create novel antitubercular peptides. The targets are analogs of viomycin, a peptide antibiotic produced by Streptomyces vinaceus and a second-line antitubercular agent that is often effective against MDR-TB. Viomycin possesses rare and unique amino acids that are crucial for biological activity but are not available for chemical synthesis. The proposal describes studies on the biochemical transformations leading to these novel amino acids, including reactions proposed to occur on peptidyl carrier (PCP) protein-bound species. Experiments are proposed to generate new peptides through targeted gene disruption and directed biosynthesis with precursor analogs added exogenously or formed in situ. Novel compounds will also be formed by controlling enzymes that decorate and fully activate the core peptide. Successfully harnessing the genes and deciphering the biochemical mechanisms involved in viomycin precursor assembly and tailoring will yield valuable information that will be translated into novel molecular tools for generating new antitubercular agents. The knowledge and methods that arise from these studies will be directly applicable to expanding the chemical diversity in other families of bioactive peptides.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069320-04
Application #
7119239
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Jones, Warren
Project Start
2003-09-30
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2008-08-31
Support Year
4
Fiscal Year
2006
Total Cost
$234,156
Indirect Cost
Name
Oregon State University
Department
Type
Schools of Pharmacy
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339