A novel cofactor-binding mode in bacterial IMP dehydrogenases explains inhibitor selectivity

Area of Science:

• Biochemistry
• Structural Biology
• Drug Discovery

Background:

• Emerging infectious diseases and antibiotic resistance necessitate novel antimicrobial agents.
• Inosine 5'-monophosphate dehydrogenase (IMPDH) is a validated target for antimicrobial drug development.
• Bacterial IMPDH possesses a unique inhibitor-binding pocket absent in human IMPDH.

Purpose of the Study:

• To elucidate the structural basis for inhibitor binding and selectivity in bacterial IMPDH.
• To understand the physiological role of the unique pocket in bacterial IMPDH.
• To explore novel strategies for antimicrobial drug development targeting bacterial IMPDH.

Main Methods:

• X-ray crystallography of bacterial IMPDH-inhibitor complexes.
• Biochemical inhibition assays.
• Structural analysis of cofactor binding.

Main Results:

• Determined structures of Bacillus anthracis, Campylobacter jejuni, and Clostridium perfringens IMPDH with various inhibitors.
• Revealed a novel NAD+ binding conformation in Vibrio cholerae IMPDH.
• Identified that the unique bacterial IMPDH pocket binds both NAD+ and inhibitors, explaining inhibitor efficacy.

Conclusions:

• The bacterial IMPDH-specific NAD+ binding mode rationalizes the efficacy of existing prokaryotic IMPDH inhibitors.
• Structural insights provide a foundation for optimizing ligands and developing new antimicrobial drugs.
• Targeting the unique bacterial IMPDH NAD+ binding pocket offers a promising strategy for combating bacterial infections.