TY - JOUR
T1 - Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis
AU - Malwal, Satish R.
AU - Chen, Lu
AU - Hicks, Hunter
AU - Qu, Fiona
AU - Liu, Weidong
AU - Shillo, Alli
AU - Law, Wen Xuan
AU - Zhang, Jianan
AU - Chandnani, Neal
AU - Han, Xu
AU - Zheng, Yingying
AU - Chen, Chun Chi
AU - Guo, Rey Ting
AU - Abdelkhalek, Ahmed
AU - Seleem, Mohamed N.
AU - Oldfield, Eric
N1 - Funding Information:
This work was supported in part by the United States Public Health Service (National Institutes of Health grants GM065307 and CA158191); the National Natural Science Foundation of China (Grants 31870790, 31470240, 31570130, and 31700057); and the Chinese Academy of Sciences (grant KFZD-SW-215-01). The authors thank Prof. D. A. Mitchell for providing bacteria, and Xinxin Feng for carrying out initial cell growth inhibition assays.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/3/14
Y1 - 2019/3/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85062331144&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062331144&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b01878
DO - 10.1021/acs.jmedchem.8b01878
M3 - Article
C2 - 30730737
AN - SCOPUS:85062331144
SN - 0022-2623
VL - 62
SP - 2564
EP - 2581
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -