【Development Research of Novel Anti-Tuberculosis Drugs Targeting a dormancy regulatory factor X】
Tuberculosis (TB) is one of the three major infectious diseases worldwide, in parallel with AIDS and malaria, and is still a threatening infectious disease for humankind. The causative bacterium is tubercle bacillus (Mycobacterium tuberculosis), which is a type of acid-fast bacterium. Even today, almost 1.7 billion people, one-quarter of the world’s population, are infected with M. tuberculosis, causing about 10 million new cases of TB and more than 1.6 million deaths each year (WHO Global Tuberculosis Report 2018). Currently, various drugs such as isoniazid are used as anti-TB drugs. However, since M. tuberculosis can enter a dormant state and stop the target metabolism of prodrugs, it is extremely difficult to treat TB with existing anti-TB drugs (Fig. 1). Given these circumstances, our collaborator, Dr. Sohkichi Matsumoto (Department of Bacteriology, Niigata University School of Medicine, HP), has revealed that dormancy regulatory factor X is the key molecule that induces dormancy (Fig. 2). Furthermore, his group found that various molecules involved in the gene expression and metabolic systems also participate in the induction of dormancy with dormancy regulatory factor X.

In this project, we aim to elucidate the molecular mechanism by which dormancy regulatory factor X, with the gene expression and metabolic systems, induces dormancy, by biochemical/molecular biological analyses and X-ray crystal structure analyses. Furthermore, we aim to develop novel anti-TB drugs that negate the abilities of entering dormancy and achieving drug tolerance, based on the three-dimensional structures of the molecules. We are conducting this project in collaboration with the Matsumoto Laboratory at Niigata University School of Medicine (HP).