Development of Antibacterials Targeting the MEP Pathway of Select Agents
Abstract
The threat of bioterrorism and the use of biological weapons against both military personnel and civilian populations has become an increasing concern for governments around the world. The 1984 Rajneeshee Salmonella attack, 2001 anthrax letter attacks, 2003 SARS outbreak, 2009 H1N1 swine flu pandemic, and the current US flu epidemic all illustrate our vulnerability to both deliberate and natural outbreaks of infectious disease and underscore the necessity of effective antimicrobial and antiviral therapeutics. The prevalence of antibiotic resistant strains and the ease by which antibiotic resistance can be engineered into bacteria further highlights the need for continued development of novel antibiotics against new bacterial targets. This research project directly addresses this need through the development of a broad spectrum inhibitor of the biothreat agents Francisella tularensis and Yersinia pestis. During this period of performance, we have optimized assays with the Y. pestis MEP synthase and the F. tularensis MEP cytidylyltransferase for use in HTS. The screening of natural product and rationally designed libraries has identified a novel inhibitor that binds to an allosteric site on MEP synthase. We confirmed this allosteric activity with the MEP synthase homologs obtained from F. tularensis and M. tuberculosis. This allosteric site has not been previously identified and represents a new site for the rational design of a new chemical class of antimicrobial drugs targeting MEP synthase. Additionally, our screening has highlighted a rationally designed bisubstrate inhibitor of MEP synthase that behaves as a tightly bound inhibitor, binding to the NADPH site and causing a conformation change that subsequently locks the inhibitor into the DXP site. And our initial screening has also identified an effective inhibitor of MEP cytidylyltransferase.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2014
- Accession Number
- ADA602353
Entities
People
- Robin Couch
Organizations
- George Mason University