过渡态理论于磺胺药物抑菌机理刍议

Discussion on the Bacteriostatic Mechanism of Sulfanilamide Compounds via Transition State Theory

依据酶过渡态理论,通过量子化学计算实验对磺胺类药物抑菌机制进行了尝试性的探讨.发现对氨基苯磺酰胺与二氢蝶酸反应的过渡态确实相似于对氨基苯甲酸与二氢蝶酸反应的过渡态结构,从而可以竞争性抑制二氢蝶酸合成酶的催化作用.计算结果能够更深刻地解释对氨基苯磺酰胺N原子上进行取代的必要性和磺酰胺结构片段的构效关系.另外,本文猜想磺胺类药物产生杀菌作用更重要的原因可能是其本身代谢产物对催化下游反应的叶酰聚谷氨酸合成酶的直接抑制作用.

Sulfonamides are the first generation antibiotics with wide bacteriostatic effects. When referring to the mechanism of bacteriostatic effect, Wood-Fields theory based on the chemical structure similarity between sulfanilamide and p-aminobenzoic acid has been broadly accepted. In this article, we put forward a complementary explanation for the bacteriostatic mechanism of sulfanilamide compounds using transition state theory. In our opinion, the transition state generated by the interaction between p-anilinesulfonamide and dihydropteroate is the mimic between p-aminobenzoic acid and dihydropteroate. Thus, dihydropteroate synthase is competitively inhibited. Based on this idea, we can reasonably explain several questions including the necessity and sufficiency of N-substitution on sulfanilamides, and the structure-activity relationship. On the other hand, we believe that the more important reason might lie in the direct inhibition of folylpolyglutamate synthetase by sulfanilamide metabolite instead of sulfanilamide per se.