Hill D L, Pittillo R F
Antimicrob Agents Chemother. 1973 Aug;4(2):125-32. doi: 10.1128/AAC.4.2.125.
Of 142 purines, purine nucleosides, and analogues tested for inhibition of growth of Escherichia coli B Hill, 45 were active. Of these, 27 were evaluated for inhibition of other E. coli lines, including those resistant to 6-thioguanine, 2-fluoroadenosine, 2,6-diaminopurine, or 6-mercaptopurine. Most toxic to the parent lines were 2-fluoroadenosine, 2-fluoroadenine, 2-fluoro-5'-deoxyadenosine, adenosine, 6-thioguanosine, 6-thioguanine, 6-mercaptopurine, 6-mercaptopurine ribonucleoside, 2-azaadenine, 2'-deoxyinosine, 6-N-aminoadenine, and inosine. Hypoxanthine was strongly inhibitory only to E. coli B Hill. Evidence regarding the substrate specificity of the three purine phosphoribosyltransferases was obtained by assaying for these enzymes in extracts of the various cell lines and by cross-resistance studies. The line selected for resistance to 6-thioguanine had low guanine phosphoribosyltransferase activity (guanosine monophosphate: pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) and was deficient in activity for xanthine and 6-thioguanine. The lines selected for resistance to 2-fluoroadenosine and 2,6-diaminopurine were deficient in adenine phosphoribosyltransferase activity (adenosine monophosphate: pyrophosphate phosphoribosyltransferase, EC 2.4.2.7), and that selected for resistance to 6-mercaptopurine had low hypoxanthine phosphoribosyltransferase activity and undetectable activity with 6-mercaptopurine as a substrate. Purine, 6-methylpurine, 2-fluoroadenine, 2,6-diaminopurine, and 2-azaadenine were classified as adenine analogues; 6-mercaptopurine and 8-aza-2,6-diaminopurine, as hypoxanthine analogues; and 6-thioguanine and 2-amino-6-chloropurine, as analogues of guanine. The inhibition of bacterial growth by hypoxanthine, inosine, 2'-deoxyinosine, or adenosine was prevented by small amounts of thiamine or by relatively high concentrations of either cytidine or uridine. Cytidine also reversed the inhibition by some purine and purine ribonucleoside analogues. Orotate phosphoribosyltransferase (OMP: pyrophosphate phosphoribosyltransferase, EC 2.4.2.10), a possible site of action for these compounds, was not inhibited directly by the toxic agents.
在对142种嘌呤、嘌呤核苷及类似物进行抑制大肠杆菌B Hill生长的测试中，有45种具有活性。其中，27种被评估对其他大肠杆菌菌株的抑制作用，包括对6 - 硫鸟嘌呤、2 - 氟腺苷、2,6 - 二氨基嘌呤或6 - 巯基嘌呤耐药的菌株。对亲本菌株毒性最大的是2 - 氟腺苷、2 - 氟腺嘌呤、2 - 氟 - 5'- 脱氧腺苷、腺苷、6 - 硫鸟苷、6 - 硫鸟嘌呤、6 - 巯基嘌呤、6 - 巯基嘌呤核糖核苷、2 - 氮杂腺嘌呤、2'- 脱氧肌苷、6 - N - 氨基腺嘌呤和肌苷。次黄嘌呤仅对大肠杆菌B Hill有强烈抑制作用。通过在各种细胞系提取物中检测这些酶以及交叉耐药性研究，获得了关于三种嘌呤磷酸核糖转移酶底物特异性的证据。选择对6 - 硫鸟嘌呤耐药的菌株鸟嘌呤磷酸核糖转移酶活性较低（鸟苷酸：焦磷酸磷酸核糖转移酶，EC 2.4.2.8），并且对黄嘌呤和6 - 硫鸟嘌呤缺乏活性。选择对2 - 氟腺苷和2,6 - 二氨基嘌呤耐药的菌株腺嘌呤磷酸核糖转移酶活性不足（腺苷酸：焦磷酸磷酸核糖转移酶，EC 2.4.2.7），而选择对6 - 巯基嘌呤耐药的菌株次黄嘌呤磷酸核糖转移酶活性较低，以6 - 巯基嘌呤为底物时检测不到活性。嘌呤、6 - 甲基嘌呤、2 - 氟腺嘌呤、2,6 - 二氨基嘌呤和2 - 氮杂腺嘌呤被归类为腺嘌呤类似物；6 - 巯基嘌呤和8 - 氮杂 - 2,6 - 二氨基嘌呤为次黄嘌呤类似物；6 - 硫鸟嘌呤和2 - 氨基 - 6 - 氯嘌呤为鸟嘌呤类似物。少量硫胺素或相对高浓度的胞苷或尿苷可阻止次黄嘌呤、肌苷、2'- 脱氧肌苷或腺苷对细菌生长的抑制作用。胞苷也可逆转一些嘌呤和嘌呤核糖核苷类似物的抑制作用。乳清酸磷酸核糖转移酶（OMP：焦磷酸磷酸核糖转移酶，EC 2.4.2.10）是这些化合物可能的作用位点，未被这些毒性剂直接抑制。
