Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Tuberculosis (TB) presents a growing global health challenge, exacerbated by multidrug- and extensively-drug resistant strains.
• Inosine 5'-monophosphate dehydrogenase 2 (IMPDH2) from Mycobacterium tuberculosis (Mtb) is a promising drug target due to its essential role in guanine nucleotide synthesis.

Purpose of the Study:

• To identify and characterize novel inhibitors of Mtb IMPDH2 with antitubercular activity.
• To elucidate the structural basis of Mtb IMPDH2 inhibition through crystallographic studies.

Main Methods:

• Screening for selective IMPDH inhibitors.
• Determination of crystal structures of Mtb IMPDH2 in various complex forms (apo, with substrate, product, and inhibitors).

Main Results:

• Seventeen selective IMPDH inhibitors exhibiting antitubercular activity were identified.
• Crystal structures revealed the binding modes of substrate, product, and three distinct inhibitors, including two with antitubercular effects.

Conclusions:

• The identified inhibitors and structural data provide a strong foundation for developing new antibiotics targeting Mtb IMPDH2.
• Structural insights facilitate structure-based drug design for novel antitubercular agents.