Isoprenoid Biosynthesis Pathway Targeting in Infectious Disease

The isoprenoid biosynthesis pathway represents a critical vulnerability in many bacterial and protozoan pathogens owing to its absence in humans. Pathogens such as Plasmodium falciparum, Mycobacterium tuberculosis and Francisella novicida rely on the non-mevalonate or methylerythritol phosphate (MEP) pathway to produce isopentenyl diphosphate (IPP), the universal precursor of isoprenoids. Key enzymes in this cascade—including 1-deoxy-D-xylulose-5-phosphate synthase (DXS), deoxyxylulose phosphate reductoisomerase (DXR), and the subsequent IspD and IspE kinases—offer selective targets for antimicrobial discovery. Recent research has advanced potent small-molecule inhibitors and lipophilic prodrugs that overcome cellular uptake barriers and achieve nanomolar potency in vitro and in vivo. Such efforts are driven by growing antimicrobial resistance, the need for broad-spectrum agents, and the global burden of malaria and tuberculosis. Structure-guided design, novel assay formats and prodrug strategies collectively underscore the translational potential of targeting isoprenoid biosynthesis in infectious disease therapy.

Research from Nature Portfolio

Innovative prodrugs of the DXR inhibitor FR900098 have been engineered to improve membrane permeability and bypass the requirement for the GlpT transporter. A lead compound demonstrated GlpT-independent antimicrobial activity against Francisella novicida, efficacy in mammalian cell infection models and protective capacity in an in vivo caterpillar model, illustrating a viable route to broad-spectrum antibiotics. In parallel, a new class of lipophilic prodrugs termed MEPicides has been developed to target Plasmodium falciparum DXR with nanomolar potency. Supplementation with isoprenoid precursors rescues parasite growth, confirming on-target activity; these compounds retained efficacy against drug-resistant isolates, proved active against sexual stages and showed safety and curative effect in murine malaria models, positioning them as promising antimalarial leads.

Isoprenoid Biosynthesis Pathway Targeting in Infectious Disease publication trend

The graph below shows the total number of articles in isoprenoid biosynthesis pathway targeting in infectious disease across all publications each year (not limited to Nature Index journals).

Technical terms

Isopentenyl diphosphate (IPP): universal five-carbon building block for isoprenoid synthesis.

MEP pathway: methylerythritol phosphate route to IPP found in many bacteria and protozoa, absent in mammals.

DXR: 1-deoxy-D-xylulose-5-phosphate reductoisomerase, the first committed enzyme of the MEP pathway.

IspD: 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase, the third enzyme in the MEP pathway.

IspE: 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase, the fourth enzyme in the MEP pathway.

Prodrug: a pharmacologically inactive compound converted in vivo to an active drug.

IC50: half-maximal inhibitory concentration, the inhibitor concentration that reduces enzyme activity by 50%.

MIC: minimum inhibitory concentration, the lowest drug concentration that prevents visible microbial growth.

References

1. Targeting Plasmodium falciparum IspD in the Methyl‑d‑erythritol Phosphate Pathway: Urea-Based Compounds with Nanomolar Potency on Target and Low-Micromolar Whole-Cell Activity. Journal of Medicinal Chemistry (2024).
2. Drug Repurposing in the Chemotherapy of Infectious Diseases. Molecules (2024).
3. Investigating Novel IspE Inhibitors of the MEP Pathway in Mycobacterium. Microorganisms (2023).
4. Lipophilic Prodrugs of FR900098 Are Antimicrobial against Francisella novicida In Vivo and In Vitro and Show GlpT Independent Efficacy. PLOS ONE (2012).
5. MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis. Scientific Reports (2017).