将隐孢子虫肌苷5'-单磷酸脱氢酶抑制剂重新用作潜在抗菌剂。
Repurposing cryptosporidium inosine 5'-monophosphate dehydrogenase inhibitors as potential antibacterial agents.
作者信息
Mandapati Kavitha, Gorla Suresh Kumar, House Amanda L, McKenney Elizabeth S, Zhang Minjia, Rao Suraj Nagendra, Gollapalli Deviprasad R, Mann Barbara J, Goldberg Joanna B, Cuny Gregory D, Glomski Ian J, Hedstrom Lizbeth
机构信息
Departments of Biology and Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia , Charlottesville, Virginia 22908, United States.
出版信息
ACS Med Chem Lett. 2014 Jun 10;5(8):846-50. doi: 10.1021/ml500203p. eCollection 2014 Aug 14.
Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the pivotal step in guanine nucleotide biosynthesis. IMPDH is a target for immunosuppressive, antiviral, and anticancer drugs, but, as of yet, has not been exploited for antimicrobial therapy. We have previously reported potent inhibitors of IMPDH from the protozoan parasite Cryptosporidium parvum (CpIMPDH). Many pathogenic bacteria, including Bacillus anthracis, Staphylococcus aureus, and Listeria monocytogenes, contain IMPDHs that should also be inhibited by these compounds. Herein, we present the structure-activity relationships for the inhibition of B. anthracis IMPDH (BaIMPDH) and antibacterial activity of 140 compounds from five structurally distinct compound series. Many potent inhibitors of BaIMPDH were identified (78% with IC50 ≤ 1 μM). Four compounds had minimum inhibitory concentrations (MIC) of less than 2 μM against B. anthracis Sterne 770. These compounds also displayed antibacterial activity against S. aureus and L. monocytogenes.
肌苷5'-单磷酸脱氢酶（IMPDH）催化鸟嘌呤核苷酸生物合成中的关键步骤。IMPDH是免疫抑制、抗病毒和抗癌药物的作用靶点，但迄今为止尚未用于抗菌治疗。我们之前报道了原生动物寄生虫微小隐孢子虫（CpIMPDH）中IMPDH的强效抑制剂。许多病原菌，包括炭疽芽孢杆菌、金黄色葡萄球菌和单核细胞增生李斯特菌，都含有IMPDH，这些化合物也应能抑制它们。在此，我们展示了五个结构不同的化合物系列中140种化合物对炭疽芽孢杆菌IMPDH（BaIMPDH）的抑制作用的构效关系以及抗菌活性。鉴定出了许多BaIMPDH的强效抑制剂（78%的IC50≤1μM）。四种化合物对炭疽芽孢杆菌Sterne 770的最低抑菌浓度（MIC）小于2μM。这些化合物对金黄色葡萄球菌和单核细胞增生李斯特菌也显示出抗菌活性。
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