Targeting Plasmodium falciparum IspD in the Methyl-d-erythritol Phosphate Pathway: Urea-Based Compounds with...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Antimicrobial Resistance Research

Background:

• The methyl-d-erythritol phosphate (MEP) pathway is essential for many human pathogens like Plasmodium falciparum (Pf) but absent in humans.
• This pathway presents a promising target for developing novel antimicrobial agents to combat resistance.

Purpose of the Study:

• To discover and characterize a new chemical class of inhibitors targeting the IspD enzyme within the MEP pathway.
• To evaluate the potential of these inhibitors as therapeutic agents against antimicrobial resistance.

Main Methods:

• Structure-activity relationship (SAR) studies were conducted to optimize inhibitor potency.
• Whole-cell activity, mode of inhibition, metabolic and plasma stability, and in vivo pharmacokinetics were assessed.
• A novel mass spectrometry (MS)-based enzymatic assay for direct IspD activity determination was developed.

Main Results:

• A new chemical class targeting IspD was identified, with inhibitors exhibiting low-nanomolar potency.
• Promising whole-cell activity, favorable metabolic and plasma stability, and suitable in vivo pharmacokinetic profiles were observed.
• A novel, enzyme-auxiliary-free MS-based assay for IspD activity was successfully developed.

Conclusions:

• A readily synthesizable compound class targeting IspD has been identified.
• These compounds demonstrate excellent activity and a promising pharmacological profile.
• The discovered inhibitors represent valuable tool compounds for advancing IspD research and developing new antimicrobials.