The relative ease of producing and distributing an agent of biological warfare makes future bioterrorist attacks an increasingly possible event. Since most of the bacterial agents used for such purposes are susceptible to current antibiotics, the clinical approach is well prepared for both treatment and prophylaxis. This luxury, however, will not last as multi-drug resistant (MDR) Yersinia pestis and Bacillus anthracis have already been described. It is particularly troublesome that the resistance determinants in the former are freely transmissible among other Enterobacteriaceae.
SPECIFIC AIMS : Data from both animal models and human subjects have documented bona fide roles for members of the MarA (AraC) family of transcription factors as microbial virulence factors. The overall goal of this application is to produce orally available small (organic) molecules (Mar inhibitors) that will target and inhibit proteins within the MarA (AraC) family. In doing so, these Mar inhibitors will act like anti-infection agents to prevent (or treat) infection of individuals in high-risk environments. RESEARCH DESIGN & METHODS: Mar inhibitors will be identified using a combination of in vitro assays and mouse models of Yersinia pseudotuberculosis infection. COMMERCIAL APPLICATIONS: Unlike that of vaccines, a novel small molecule anti-infection therapeutic, i.e., a Mar inhibitor, offers the advantage of being able to target multiple pathogens simultaneously. This product would not have inherent antimicrobial activity and as such would not be expected to promote resistance development. This product would find use in high-risk environments, e.g., to protect the community during a bioterrorist attack or as a prophylactic to protect soldiers in hostile environments. MARKET POTENTIAL: It has been estimated that more than $200 million was spent on antibiotics in response to the isolated anthrax attacks in the fall of 2001. Thus, a novel biodefense antiinfection therapeutic represents a substantial market opportunity and public health need.
| Garrity-Ryan, Lynne K; Kim, Oak K; Balada-Llasat, Joan-Miquel et al. (2010) Small molecule inhibitors of LcrF, a Yersinia pseudotuberculosis transcription factor, attenuate virulence and limit infection in a murine pneumonia model. Infect Immun 78:4683-90 |
| Kim, Oak K; Garrity-Ryan, Lynne K; Bartlett, Victoria J et al. (2009) N-hydroxybenzimidazole inhibitors of the transcription factor LcrF in Yersinia: novel antivirulence agents. J Med Chem 52:5626-34 |
