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Expanding the Chemical Space of Reverse Fosmidomycin Analogs
Talea Knak1, Sana Takada2, Boris Illarionov3
1Institute of Pharmaceutical and Medicinal Chemistry, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
ACS Medicinal Chemistry Letters
|January 15, 2025
Summary
Novel fosmidomycin analogs targeting the essential DXR enzyme show potent inhibition against key pathogens like Plasmodium falciparum. However, achieving effective cellular activity remains a challenge, requiring further optimization.
Area of Science:
- Medicinal Chemistry
- Antimicrobial Drug Discovery
- Enzyme Inhibition
Background:
- Multidrug-resistant pathogens present a significant global health threat, driving the need for novel therapeutic strategies.
- Identifying drug targets absent in humans, such as 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), is crucial for developing effective antimicrobials.
- Fosmidomycin, a known DXR inhibitor, serves as a benchmark for developing new antibacterial and antimalarial agents.
Purpose of the Study:
- To synthesize and evaluate novel reverse thia analogs of fosmidomycin as inhibitors of DXR.
- To assess the inhibitory activity of these analogs against DXR orthologs from Plasmodium falciparum, Escherichia coli, and Mycobacterium tuberculosis.
- To investigate the structural basis for DXR inhibition and explore challenges in translating target inhibition to cellular activity.
Main Methods:
- Chemical synthesis of novel phosphonohydroxamic acid analogs.
- Enzyme inhibition assays against purified DXR orthologs.
- In vitro antimicrobial susceptibility testing against relevant pathogens.
- X-ray crystallography to determine the binding mode of inhibitors with PfDXR.
Main Results:
- Several novel analogs demonstrated potent inhibition of DXR across multiple pathogen species, outperforming fosmidomycin.
- Compounds with large α-phenyl substituents showed significant DXR inhibitory activity.
- Despite nanomolar enzyme inhibition, most analogs exhibited weak or no in vitro growth inhibition of the pathogens.
- Crystallographic data revealed compounds 12a and 12b induce an open PfDXR conformation, with selective binding of S-enantiomers.
Conclusions:
- Novel reverse thia analogs of fosmidomycin are potent inhibitors of the essential DXR enzyme.
- Translating potent DXR inhibition into significant antimicrobial activity is challenging and requires further investigation.
- Structural insights highlight the importance of enzyme conformation and stereochemistry in inhibitor binding.
- Future drug development necessitates advanced structural optimization and pharmacokinetic evaluations.
