Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis
| Autor: | Rey-Ting Guo, Xu Han, Alli Shillo, Eric Oldfield, Weidong Liu, Ahmed Abdelkhalek, Mohamed N. Seleem, Fiona Qu, Hunter Hicks, Lu Chen, Satish R. Malwal, Wen Xuan Law, Chun-Chi Chen, Jianan Zhang, Yingying Zheng, Neal Chandnani |
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| Rok vydání: | 2019 |
| Předmět: |
Microbial Sensitivity Tests
Bacillus subtilis Gram-Positive Bacteria 01 natural sciences Article Bacterial cell structure 03 medical and health sciences chemistry.chemical_compound Farnesyl diphosphate synthase Cell Wall Drug Discovery Humans 030304 developmental biology 0303 health sciences Diphosphonates biology Mycobacterium smegmatis Quinones Blood Proteins biology.organism_classification Anti-Bacterial Agents 0104 chemical sciences Bacillus anthracis Quinone 010404 medicinal & biomolecular chemistry Heptaprenyl diphosphate synthase chemistry Biochemistry biology.protein Molecular Medicine Growth inhibition |
| Zdroj: | Journal of Medicinal Chemistry. 62:2564-2581 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b01878 |
| Popis: | We report that alkyl-subsituted bisphosphonates have activity against Bacillus anthracis Sterne (0.40 µg/mL), Mycobacterium smegmatis (1.4 µg/mL), Bacillus subtilis (1.0 µg/mL) and Staphylococcus aureus (13 µg/mL). In many cases, there is no effect of serum binding, as well as low activity against a human embryonic kidney cell line. Targeting of isoprenoid biosynthesis is involved with74 having IC(50) values of ~100 nM against heptaprenyl diphosphate synthase and 200 nM against a farnesyl diphosphate synthase. Bacillus subtilis growth inhibition was rescued by addition of farnesyl diphosphate, menaquinone-4 (MK-4) or undecaprenyl diphosphate (UP) and the combination of MK-4 plus UP resulted in a 25x increase in ED(50), indicating targeting of both quinone and cell wall biosynthesis. Clostridioides difficile was inhibited by 74 and since this organism does not synthesize quinones, cell wall biosynthesis is the likely target. We also solved three X-ray structures of inhibitors bound to octaprenyl diphosphate and/or undecaprenyl diphosphate synthases. |
| Databáze: | OpenAIRE |
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