The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives

Abstract

Isoprenoids, a diverse class of natural products, are present in all living organisms. Their two universal building blocks are synthesized via two independent pathways: the mevalonate pathway and the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway. The presence of the latter in pathogenic bacteria and its absence in humans make all its enzymes suitable targets for the development of novel antibacterial drugs. (E)-4-Hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), the last intermediate of this pathway, is a natural ligand for the human Vγ9Vδ2 T cells and the most potent natural phosphoantigen known to date. Moreover, 5-hydroxypentane-2,3-dione, a metabolite produced by Escherichia coli 1-deoxy-d-xylulose 5-phosphate synthase (DXS), the first enzyme of the MEP pathway, structurally resembles (S)-4,5-dihydroxy-2,3-pentanedione, a signal molecule implied in bacterial cell communication. In this review, we shed light on the diversity of potential uses of the MEP pathway in antibacterial therapies, starting with an overview of the antibacterials developed for each of its enzymes. Then, we provide insight into HMBPP, its synthetic analogs, and their prodrugs. Finally, we discuss the potential contribution of the MEP pathway to quorum sensing mechanisms. The MEP pathway, providing simultaneously antibacterial drug targets and potent immunostimulants, coupled with its potential role in bacterial cell–cell communication, opens new therapeutic perspectives.

An activity-based probe for antimicrobial target DXP synthase, a thiamin diphosphate-dependent enzyme

“…This enzyme catalyzes the thiamin diphosphate (ThDP)-dependent formation of DXP from pyruvate and D-glyceraldehyde 3-phosphate (D-GAP). Absent in humans but widespread in high priority Gram-negative bacterial pathogens (Heuston et al, 2012;World Health Organization, 2022;Allamand et al, 2023), DXP is a branchpoint metabolite that serves as a precursor to vitamins B1 (ThDP) and B6 (pyridoxal phosphate, PLP), as well as isoprenoids biosynthesized via the methylerythritol phosphate (MEP) pathway (Figure 1) (Rodríguez-Concepción and Boronat, 2002;Hill, Sayer, and Spenser, 1989;M. Rohmer et al, 1993;David et al, 1981).…”

Target-Directed Dynamic Combinatorial Chemistry Affords Binders of Mycobacterium Tuberculosis IspE

“…6 While all enzymes of the MEP-pathway are considered potential antibiotic drug targets, few inhibitors have been reported since its discovery in the 1990s. [9][10][11] This pathway is vital for critical pathogens, such as Mycobacterium tuberculosis (Mtb), and Gram-negative bacteria to afford the essential isoprenoid precursors isopentenyl diphosphate (IDP) and dimethylallyl diphosphate (DMADP). 12 Moreover, it is absent in mammals, where the mevalonate pathway yields the same building blocks, making target-related toxicity less of a concern.…”

Design, Synthesis and Bioactivity Evaluation of Heterocycle-Containing Mono- and Bisphosphonic Acid Compounds

“…The 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, which is widespread in bacteria and plants but absent in mammals [1], has gained significant attention in recent years since seven key enzymes are involved in this pathway (Figure 1), which can serve as new targets to develop novel herbicides and antibacterial agents [2,3]. The products of the MEP pathway, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), are crucial precursors for the synthesis of various isoprenoids [4].…”