Bacterial Pathogens Program
|Lead Investigators||Peter Dedon|
|MIT Investigators||Ram Sasisekharan|
|Associate MIT Investigators||Steven Tannenbaum|
|Affiliate MIT Investigators||Bevin Engelward|
|Singapore Co-Investigators||Sylvie Alonso, Nam Joon Cho, Vincent Chow, Thomas Dick, Jagath C Rajapakse|
To complete the full spectrum of infectious diseases, the ID IRG has a major research thrust addressing bacterial pathogens, which represent a major cause of morbidity and mortality globally. The emergence of drug-resistance in virtually every major bacterial pathogen, such as extreme drug-resistant Pseudomonas aeruginosa in Singaporean hospitals and drug resistant strains of Mycobacterium tuberculosis (Mtb) in Southeast Asia and Singapore, is outpacing the development of new antibiotics. The scale of this problem is illustrated by the fact that over one-third of the world’s population is infected with Mtb, with the majority of infections existing in a poorly understood asymptomatic latent or persistent form that both escapes detection by the immune system and confers significant drug resistance to the Mtb organisms.
To deal with these challenges, a team of MIT, NUS and NTU researchers has embarked on a translational program to discover fundamental mechanisms of bacterial adaptation, survival and persistence in the host and then to exploit these mechanisms as targets for antibiotic development. This approach is illustrated by the poorly understood phenomenon of persistence and latency in Mtb infections, in which the bacterium enters a non-replicative and drug resistance state for decades-long survival in the host. Using innovative convergent technologies, ID IRG researchers have discovered a novel molecular mechanism that mycobacteria use to enter this latent state, in which the cells reprogram a system of tRNA modifications that controls selective translation of critical latency-inducing proteins. To facilitate development of new antibiotics that target this and other critical survival pathways in Mtb, ID IRG researchers are also developing novel fluorescence-based phenotypic screening tools to search for drug candidates that are both capable of passing through the uniquely impermeable cell wall of Mtb and of reacting with the target proteins. ID IRG researchers have discovered that these survival and response pathways are common to all bacterial pathogens, which has led to a pipeline of both drug screening and structure-based drug design efforts. Researchers continue this innovative infectious disease research with discoveries made in other bacterial survival and host response pathways.