Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis

Satish R. Malwal, Lu Chen, Hunter Hicks, Fiona Qu, Weidong Liu, Alli Shillo, Wen Xuan Law, Jianan Zhang, Neal Chandnani, Xu Han, Yingying Zheng, Chun Chi Chen, Rey Ting Guo, Ahmed Abdelkhalek, Mohamed N. Seleem, Eric Oldfield

Research output: Contribution to journalArticle

Abstract

We report that alkyl-substituted 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 with 74 having IC50 values of ∼100 nM against heptaprenyl diphosphate synthase and 200 nM against farnesyl diphosphate synthase. B. subtilis growth inhibition was rescued by addition of farnesyl diphosphate, menaquinone-4 (MK-4), or undecaprenyl phosphate (UP), and the combination of MK-4 and UP resulted in a 25× increase in ED50, 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.

Original languageEnglish (US)
Pages (from-to)2564-2581
Number of pages18
JournalJournal of Medicinal Chemistry
Volume62
Issue number5
DOIs
StatePublished - Mar 14 2019

Fingerprint

undecaprenyl pyrophosphate synthetase
trans-hexaprenyltranstransferase
Diphosphonates
Bacillus subtilis
Cell Wall
Geranyltranstransferase
Mycobacterium smegmatis
Bacillus anthracis
Quinones
Diphosphates
Terpenes
Inhibitory Concentration 50
Staphylococcus aureus
X-Rays
Kidney
Cell Line
Growth
Serum
undecaprenyl phosphate
benzoquinone

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis. / Malwal, Satish R.; Chen, Lu; Hicks, Hunter; Qu, Fiona; Liu, Weidong; Shillo, Alli; Law, Wen Xuan; Zhang, Jianan; Chandnani, Neal; Han, Xu; Zheng, Yingying; Chen, Chun Chi; Guo, Rey Ting; Abdelkhalek, Ahmed; Seleem, Mohamed N.; Oldfield, Eric.

In: Journal of Medicinal Chemistry, Vol. 62, No. 5, 14.03.2019, p. 2564-2581.

Research output: Contribution to journalArticle

Malwal, SR, Chen, L, Hicks, H, Qu, F, Liu, W, Shillo, A, Law, WX, Zhang, J, Chandnani, N, Han, X, Zheng, Y, Chen, CC, Guo, RT, Abdelkhalek, A, Seleem, MN & Oldfield, E 2019, 'Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis', Journal of Medicinal Chemistry, vol. 62, no. 5, pp. 2564-2581. https://doi.org/10.1021/acs.jmedchem.8b01878
Malwal, Satish R. ; Chen, Lu ; Hicks, Hunter ; Qu, Fiona ; Liu, Weidong ; Shillo, Alli ; Law, Wen Xuan ; Zhang, Jianan ; Chandnani, Neal ; Han, Xu ; Zheng, Yingying ; Chen, Chun Chi ; Guo, Rey Ting ; Abdelkhalek, Ahmed ; Seleem, Mohamed N. ; Oldfield, Eric. / Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 5. pp. 2564-2581.
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AU - Law, Wen Xuan

AU - Zhang, Jianan

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AU - Abdelkhalek, Ahmed

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