Project leader: Michael Serrano-Wu
Key collaborators: Deborah Hung

FadD32 is an essential enzyme for biosynthesis of mycolic acids, which comprise an integral component of the cell envelope in Mycobacterium tuberculosis. Broad scientists have recently discovered potent inhibitors of FadD32 using a full arsenal of genetic, protein, and small-molecule tools to identify new treatment modalities. These efforts have uncovered additional opportunities to inhibit M. tuberculosis during both its replicating and non-replicating phases. This “dual-hit” approach may improve treatment outcomes especially versus drug-resistant strains.

Despite coordinated efforts to improve availability of standard of care, tuberculosis (TB) is still one of the leading causes of death by infectious diseases worldwide, killing an estimated 2 million people annually. Strains of M. tuberculosis have now emerged that are not only resistant to both first- and second-line drugs, but are also resistant to all known TB drugs, thus posing a serious threat to the management of TB and human health.

Populations where HIV is prevalent are especially susceptible to TB co-infection; in 2010, 350,000 people died as a result of TB and HIV co-infection.

Discovery of shorter, effective treatment regimens with broader coverage across drug-resistant TB strains is essential for continued progress in global TB management. At the Broad, scientists are keenly focused on characterizing novel mechanisms to combat TB, using a full arsenal of genetic, protein, and small-molecule tools to identify new treatment modalities. Broad researchers have recently discovered novel inhibitors of FadD32, a key enzyme in mycolic acid biosynthesis, and are actively pursuing this target as a new modality in TB combination therapy.

They have also developed novel screens to interrogate TB biology throughout its lifecycle, including the non-replicating phase when current therapy can be particularly ineffective. Optimization of hits from these screens, especially those with dual activity against replicating and non-replicating phases of the TB lifecycle, is another focus within the Broad’s TB therapeutics portfolio.

Ultimately, the goal of the Broad’s TB therapeutics effort is to rigorously elucidate biological pathways that will render TB most susceptible to therapeutic agents, and to optimize molecules that will allow therapeutic hypotheses to be evaluated in humans.