Over 40 Years of Fosmidomycin Drug Research: A Comprehensive Review and Future Opportunities

Abstract

To address the continued rise of multi-drug-resistant microorganisms, the development of novel drugs with new modes of action is urgently required. While humans biosynthesize the essential isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) via the established mevalonate pathway, pathogenic protozoa and certain pathogenic eubacteria use the less well-known methylerythritol phosphate pathway for this purpose. Important pathogens using the MEP pathway are, for example, Plasmodium falciparum, Mycobacterium tuberculosis, Pseudomonas aeruginosa and Escherichia coli. The enzymes of that pathway are targets for antiinfective drugs that are exempt from target-related toxicity. 2C-Methyl-D-erythritol 4-phosphate (MEP), the second enzyme of the non-mevalonate pathway, has been established as the molecular target of fosmidomycin, an antibiotic that has so far failed to be approved as an anti-infective drug. This review describes the development and anti-infective properties of a wide range of fosmidomycin derivatives synthesized over the last four decades. Here we discuss the DXR inhibitor pharmacophore, which comprises a metal-binding group, a phosphate or phosphonate moiety and a connecting linker. Furthermore, non-fosmidomycin-based DXRi, bisubstrate inhibitors and several prodrug concepts are described. A comprehensive structure–activity relationship (SAR) of nearly all inhibitor types is presented and some novel opportunities for further drug development of DXR inhibitors are discussed.

Design and synthesis of fosmidomycin analogs containing aza‐linkers and their biological activity evaluation

“…The results of the antiplasmodial activity test for the compounds are show in Fig. 4, in which the control compounds FOS and FR have IE of 47.40% and 67.48%, respectively, similar to the reported activities of FOS and FR 10 . Interestingly, although most of the synthesized compounds show no meaningful activity, compounds 10f and 10g , which bear the N ‐substituents 4‐CH 3 ‐phenylethyl and 4‐F‐phenylethyl, respectively, exhibit significant P. falciparum 3D7 inhibition effects with IE of 71.49% and 73.49%, respectively, better than those of FOS and FR.…”

“…Incorporation of one nitrogen atom into the linker is intended to increase similar hydrogen‐bonding interactions to that occurring in the oxa‐linker FOS analogs previously reported 17 . The use of retro‐hydroxamate in place of hydroxamate is a common strategy for the design of new FOS analogs with comparable FOS‐like activities 10 . These facts are the basis of the design strategy in this work for generating aza‐linker FOS analogs with the desired activity.…”

“…Two natural products, fosmidomycin (FOS) 8 and its acetyl analog FR900098 (FR) 9 isolated from Streptomyces species (Fig. 1(B)), have proven significant inhibitory effects on the IspC enzymes from Escherichia coli , Mycobacterium tuberculosis and Plasmodium falciparum 10 . FOS in particular has been used in clinical trials for the treatment of malaria in combination with other drugs 11,12 .…”

“…Although in recent years a lot of FOS analogs have been reported, all were tested against bacteria or P. falciparum with the intention to find new anti‐infective agents for use in clinic 10 . None were tested on plants for the purposes of herbicide development.…”

“…1(B)), have proven significant inhibitory effects on the IspC enzymes from Escherichia coli, Mycobacterium tuberculosis and Plasmodium falciparum. 10 FOS in particular has been used in clinical trials for the treatment of malaria in combination with other drugs. 11,12 Despite their promising biological activities, both FOS and FR have some serious drawbacks such as high hydrophilicity, short half-life and hence low bioavailability, preventing or limiting their use in practice.…”