Di Giacomo B, Tarzia G, Bedini A, Gatti G, Bartoccini F, Balsamini C, Tontini A, Baffone W, Di Modugno E, Felici A
Istituto di Chimica Farmaceutica, Università di Urbino, Italy.
Farmaco. 2002 Apr;57(4):273-83. doi: 10.1016/s0014-827x(02)01207-7.
New penicillin, penicillin sulfone and sulfoxide derivatives bearing a C-6-alkyliden substituent were prepared. Their chemical synthesis, in vitro antibacterial activity and inhibition properties against two selected enzymes representing Class A and C beta-lactamases are reported. Compounds 3a-c, 7a-c were able to inhibit either TEM-1 (a Class A enzyme, from Escherichia coli) or P-99 (a Class C enzyme, from E. cloacae), or both enzymes, when tested in competition experiments using nitrocefin as the reporter substrate. However, when tested in combination with amoxicillin, the same compounds did not show synergistic effects against E. coli and E. cloacae strains producing TEM-1 and P99 enzymes, respectively. This finding is most likely related to poor penetration through the bacterial cell wall, as shown by using a more permeable isogenic E. coli strain. Interestingly, a synergistic effect against a strain of S. aureus which produces PC1-enzyme (a Class A beta-lactamase) was observed for compound 3a when used in combination with amoxicillin.
制备了带有C-6-亚烷基取代基的新型青霉素、青霉素砜和亚砜衍生物。报道了它们的化学合成、体外抗菌活性以及对两种分别代表A类和C类β-内酰胺酶的选定酶的抑制特性。在使用硝噻吩作为报告底物的竞争实验中测试时，化合物3a-c、7a-c能够抑制TEM-1（一种来自大肠杆菌的A类酶）或P-99（一种来自阴沟肠杆菌的C类酶），或两种酶。然而，当与阿莫西林联合测试时，相同的化合物对分别产生TEM-1和P99酶的大肠杆菌和阴沟肠杆菌菌株没有显示出协同作用。如使用渗透性更强的同基因大肠杆菌菌株所示，这一发现很可能与通过细菌细胞壁的渗透性差有关。有趣的是，当化合物3a与阿莫西林联合使用时，观察到对产生PC1酶（一种A类β-内酰胺酶）的金黄色葡萄球菌菌株有协同作用。
