γ‐Substituted Bis(pivaloyloxymethyl)ester Analogues of Fosmidomycin and FR900098

Kurz, Thomas; Behrendt, Christoph; Pein, Miriam; Kaula, Uwe; Bergmann, Bärbel; Walter, Rolf D.

doi:10.1002/ardp.200700107

Cited by 14 publications

(8 citation statements)

References 22 publications

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“…While FSM is safe and well tolerated, it is also rapidly cleared (24,25), and its biological spectrum of activity is limited due to cellular exclusion in many organisms, including M. tuberculosis and T. gondii (10,29). Many attempts to modify FSM in the hopes of improving efficacy against the enzyme or the organism have been disappointing (32,33,35,50,51). Our studies provide definitive evidence that the primary intracellular target of FSM is Dxr.…”

Section: Discussionmentioning

confidence: 70%

“…These limitations have led to substantial efforts to develop more cell-permeable analogs of FSM or its highly related analog FR900098 (30)(31)(32)(33)(34)(35). Because many FSM derivatives are prodrugs that require intracellular activation, it is often impossible to test the efficacy of these compounds directly on the Dxr target enzyme in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Because of this impermeability, FSM is ineffective against many potential pathogens, such as Toxoplasma gondii (29) and M. tuberculosis (10). Thus, substantial efforts have been made to develop more cell-permeable analogs of FSM or its highly related analog, FR900098 (30)(31)(32)(33)(34)(35).…”

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confidence: 99%

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Resistance to the Antimicrobial Agent Fosmidomycin and an FR900098 Prodrug through Mutations in the Deoxyxylulose Phosphate Reductoisomerase Gene ( dxr )

Armstrong

Meyers

Imlay

et al. 2015

Antimicrob Agents Chemother

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There is a pressing need for new antimicrobial therapies to combat globally important drug-resistant human pathogens, including Plasmodium falciparum malarial parasites, Mycobacterium tuberculosis, and Gram-negative bacteria, including Escherichia coli. These organisms all possess the essential methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, which is not found in humans. The first dedicated enzyme of the MEP pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr), is inhibited by the phosphonic acid antibiotic fosmidomycin and its analogs, including the N-acetyl analog FR900098 and the phosphoryl analog fosfoxacin. In order to identify mutations in dxr that confer resistance to these drugs, a library of E. coli dxr mutants was screened at lethal fosmidomycin doses. The most resistant allele (with the S222T mutation) alters the fosmidomycin-binding site of Dxr. The expression of this resistant allele increases bacterial resistance to fosmidomycin and other fosmidomycin analogs by 10-fold. These observations confirm that the primary cellular target of fosmidomycin is Dxr. Furthermore, cell lines expressing Dxr-S222T will be a powerful tool to confirm the mechanisms of action of future fosmidomycin analogs.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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Resistance to the Antimicrobial Agent Fosmidomycin and an FR900098 Prodrug through Mutations in the Deoxyxylulose Phosphate Reductoisomerase Gene ( dxr )

Armstrong

Meyers

Imlay

et al. 2015

Antimicrob Agents Chemother

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“…However, the high recurrence rate necessitated the combination with established second antimalarial [59][60][61]. More recently, a variety of aryl and alkyl derivatives of fosmidomycin (13) have been synthesized [51, 53, [62][63][64][65][66][67][68][69]. Some derivatives showed improved IC50 values, in the single digit nanomolar range, for IspC from P. falciparum.…”

Section: Elucidation Of the Non-mevalonate Pathway Using Genomicsmentioning

confidence: 99%

Biochemistry of the non-mevalonate isoprenoid pathway

Gräwert

Groll

Rohdich

et al. 2011

Cell. Mol. Life Sci.

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The non-mevalonate pathway of isoprenoid (terpenoid) biosynthesis is essential in many eubacteria including the major human pathogen, Mycobacterium tuberculosis, in apicomplexan protozoa including the Plasmodium spp. causing malaria, and in the plastids of plants. The metabolic route is absent in humans and is therefore qualified as a promising target for new anti-infective drugs and herbicides. Biochemical and structural knowledge about all enzymes involved in the pathway established the basis for discovery and development of inhibitors by high-throughput screening of compound libraries and/or structure-based rational design.

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“…It has an anti-malarial action and well tolerated in the human beings. Modification in the simple structure of the fosmidomycin derivative to improve its drug characteristics has been challenging (Kurz et al 2007;Ortmann et al 2007;Tahar & Basco 2007;Wiesner et al 2007;Haemers et al 2008). In the current era of drug design and discovery, bridging the gap between the computational and a medicinal chemist is indispensable for synthesizing a blockbuster drug molecule.…”

Section: Introductionmentioning

confidence: 99%

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

Wadood

Ghufran

Hassan

et al. 2016

Pharmaceutical Biology

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Fosmidomycin is a promising DXR inhibitor, which showed safety as well as efficacy against Plasmodium falciparum malaria in clinical trials. However, due to its poor oral bioavailability and non-drug-like properties, the focus of medicinal chemists is to develop inhibitors with improved pharmacological properties. Objective: This study described the computational design of new and potent inhibitors for deoxyxylulose 5-phosphate reductoisomerase and the prediction of their pharmacokinetic and pharmacodynamic properties. Material and methods: A complex-based pharmacophore model was generated from the complex X-ray crystallographic structure of PfDXR using MOE (Molecular Operating Environment). Furthermore, MOE-Dock was used as docking software to predict the binding modes of hits and target enzyme.Results: Finally, 14 compounds were selected as new and potent inhibitors of PfDXR on the basis of pharmacophore mapping, docking score, binding energy and binding interactions with the active site residues of the target protein. The predicted pharmacokinetic properties showed improved permeability by efficiently crossing blood-brain barrier. While, in silico promiscuity binding data revealed that these hits also have the ability to bind with other P. falciparum drug targets. Discussion and conclusion: In conclusion, innovative scaffolds with novel modes of action, improved efficacy and acceptable physiochemical/pharmacokinetic properties were computationally identified.ARTICLE HISTORY

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γ‐Substituted Bis(pivaloyloxymethyl)ester Analogues of Fosmidomycin and FR900098

Cited by 14 publications

References 22 publications

Resistance to the Antimicrobial Agent Fosmidomycin and an FR900098 Prodrug through Mutations in the Deoxyxylulose Phosphate Reductoisomerase Gene ( dxr )

Resistance to the Antimicrobial Agent Fosmidomycin and an FR900098 Prodrug through Mutations in the Deoxyxylulose Phosphate Reductoisomerase Gene ( dxr )

Biochemistry of the non-mevalonate isoprenoid pathway

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

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