New anti-infectives based on novel chemical scaffolds are vital to biodefense strategy primarily because they will be effective against both natural and engineered resistant forms of bioterrorist microbes. Our research efforts are focused on the discovery and development of novel therapeutic agents for the treatment of Ebola virus infection, and against Bacillus anthracis and Burkholderia pseudomallei.

Development of Entry Inhibitors Against Ebola Virus Infection:

Ebola virus (EBOV) is an aggressive pathogen that causes highly lethal viral hemorrhagic fever syndrome. EBOV is believed to be indigenous to Africa and causes periodic outbreaks of severe viral hemorrhagic fevers in the continent, with a 50-90% mortality rate in infected patients. It has been classified as a Category A bioweapons agent by the Centers for Disease Control and Prevention (CDC). Currently, there is no FDA approved vaccine or antiviral drug (not even an experimental one) that is effective against EBOV infections in humans. The rapid progression of EBOV infection also offers little opportunity to develop acquired immunity. Therefore, there is a critical need for development of effective therapies to respond to post-exposure prophylaxis during outbreaks of EBOV infection, and to counter potential acts of bioterrorism. We are trying to block the entry step of the EBOV infection. We have generated pseudotype virus expressing EBOV envelope glycoproteins as a surrogate model to screen for inhibitors that target the viral entry process in our BSL2 laboratory. Microbiotix is utilizing two main platforms for developing entry inhibitors against EBOV infection, which are (1) high-throughput screening of a library of small molecules to discover unique anti-EBOV drug candidate structures and (2) structure-based drug design approaches to target the cellular cysteine proteases cathepsin B and cathepsin L that are essential for EBOV infection.

Sensing Biowarfare Agents by Surface-enhanced Raman

The goal of this project is to develop a platform tool based on surface-enhanced Raman scattering (SERS) microscopy for the simultaneous rapid detection and identification of a broad range of category A-C priority bacterial pathogens. The SERS microscopic diagnostic platform will provide rapid, reagentless, specific identification of species within minutes, and will be developed as a portable device for field use. We are developing a reference base for SERS spectra. We are also in the process of developing rapid, robust methods of enriching bacteria from clinical samples for SERS and optimizing the SERS substrate performance.

Development of Screens for Bacillus anthracis Targets

The goal of this research is to discover and develop novel antibiotics effective against B. anthracis, including resistant forms of this organism, for biodefense. Our strategy is to screen for novel inhibitors against DNA polymerase III C (pol lII C) and topoisomerase IV (topo IV). Using the non-pathogenic B. anthracis Sterne strain, we have developed a permeable-cell DNA replication pathway screen and are screening our library of small molecules to discover unique drug candidates against B. anthracis infections.

Discovery of Burkholderia pseudomallei Therapeutics for Biodefense

B. pseudomallei is a bioterrorist threat. With the best current therapies, lethality is typically as high as 40%. The overall goal of this application is the development of new drugs against this organism. We are exploiting the high sequence similarity between B. pseudomallei and its less virulent relative P. aeruginosa and are in the in process of developing innovative screens for the rapid and safe discovery of effective therapeutic agents. The two species are similar in genome size and composition, with nucleotide and amino acid sequence identities for many genes in the 50-70% range, and in their mechanisms of drug resistance.