Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
Science. 2010 Nov 5;330(6005):831-5. doi: 10.1126/science.1191175.
The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial β-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.
常见的结肠癌化疗药物 CPT-11 的剂量限制副作用是严重腹泻,这是由共生细菌β-葡萄糖醛酸酶引起的,这些酶会在肠道中使药物重新激活。我们试图在不杀死对人类健康至关重要的共生细菌的情况下靶向这些酶。通过高通量筛选鉴定出了强效的细菌β-葡萄糖醛酸酶抑制剂,并且这些抑制剂对同源的哺乳动物酶没有影响。晶体结构表明,选择性基于细菌β-葡萄糖醛酸酶特有的环。抑制剂在需氧和厌氧活菌中对酶靶标非常有效,但既不会杀死细菌也不会伤害哺乳动物细胞。最后,抑制剂的口服给药可保护小鼠免受 CPT-11 引起的毒性。因此,可以设计药物来抑制必需微生物共生体中不良的酶活性,以提高化疗效果。