Despite the availability of effective antibiotics, TB is the leading worldwide killer. While current drugs work, they are far from optimal. Therapy is lengthy. Patients who stop treatment before six months have a significant risk of relapse even though their symptoms subside months earlier.
In addition, drug resistance strains have arisen rapidly and, in many parts of the world, represent a substantial fraction of new infections
Strains carrying multiple drug resistance determinants are difficult and, at times, impossible to treat with currently available drugs. Clearly, new antibiotics that act more rapidly and are active against drug resistant strains could make a profound difference in controlling the TB epidemic.
The TB Structural Genomics Consortium (TBSGC) started fifteen years ago as an effort to produce a diverse set of mycobacterial protein structures . However, since that time, our goals have evolved. Instead of emphasizing the numbers of structures solved, we have moved to focusing on proteins that could be potential antibiotic targets.
Importantly, we are leveraging chemical biology and bacterial genetics to provide insights into function from a protein level to a whole organism level, to aid in inhibitor design for attractive targets. During the last funding period, this strategy has been extremely successful. In addition, to making significant biological breakthroughs, we have also developed compounds that are in late preclinical development as potential anti-TB drugs.
In this renewal application, we propose to continue our focus on vulnerabilities of Mtb and work to increase our emphasis on the variety of tools we use to understand and exploit proteins that could serve as antibiotic targets. Throughout our program, we have continually adapted our approach and enlisted new personnel to allow us to exploit the most exciting biological areas with the most valuable cutting edge techniques. Here, again, we have made several changes within our program that both reinforce existing and create new collaborations. Furthermore, we continue to leverage our many interactions with external groups that add value to our research. Significantly, the TBSGC continues to occupy a unique niche in the TB drug development community.
