ReviewKeynoteTargeting isocitrate lyase for the treatment of latent tuberculosis

- Isocitrate lyase (ICL) is essential to growth and survival of Mycobacterium tuberculosis (Mtb).
- ICL is involved in Mtb glyoxylate and methylisocitrate cycles, and may play a part in Mtb antibiotic resistance development.
- The roles of the two Mtb ICL isoforms are not fully understood.
- Reported ICL inhibitors not suitable as drug candidates; challenges include polarity, size of binding pocket and selectivity.
- Further work is required to fully validate ICL as a therapeutic target.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that can remain dormant for many years before becoming active. One way to control and eliminate TB is the identification and treatment of latent TB, preventing infected individuals from developing active TB and thus eliminating the subsequent spread of the disease. Isocitrate lyase (ICL) is involved in the mycobacterial glyoxylate and methylisocitrate cycles. ICL is important for the growth and survival of M. tuberculosis during latent infection. ICL is not present in humans and is therefore a potential therapeutic target for the development of anti-TB agents. Here, we explore the evidence linking ICL to persistent survival of M. tuberculosis. The structure, mechanism and inhibition of the enzyme is also discussed.