Structure-and-mechanism-based design and discovery of type II Mycobacterium Tuberculosis dehydroquinate dehydratase inhibitors

Mycobacterium tuberculosis is the causative agent of tuberculosis, a lethal infection disease that attacks the lungs. Now it becomes the major global health risk because of very long latent period, the persistent increase of new cases, and the emergence of multidrug-resistant and extensively drug-resistant strains. Therefore, there is an urgent need for the development of new, safe and more efficient tuberculosis drugs. The shikimate pathway has been considered as the attractive drug target due to its essentiality in algae, higher plants, bacteria, and fungi, but absence from mammals. In this review, we focus on the recent development of a wide variety of inhibitors of type II Mycobacterium tuberculosis dehydroquinate dehydratase, the third enzyme of this pathway. The structural and mechanistic features of the enzyme for the design and discovery of the inhibitors have been described. The key factors on the structure, binding, and affinity of the inhibitors have been also highlighted. This may direct the further development of type II Mycobacterium tuberculosis dehydroquinate dehydratase inhibitors as potent tuberculosis drugs.