pH对β-内酰胺酶抑制剂抑酶作用的影响

Effect of p H on β-lactamase inhibitors against β- lactamases

选择舒巴坦 (sulbactam )和克拉维酸 (clavulanic acid)为研究对象 ,考察在不同 p H条件下 (6 .0、7.0、8.0 )两者对三种 β-内酰胺酶 (TEM- 2、SHV- 1、OXA- 3)抑酶作用的变化。结果表明 ,克拉维酸对三种酶的抑制效力均较好 ,舒巴坦对 OXA- 3酶的抑制效力远较其它两种酶差 ,且舒巴坦对 p H的敏感性强于克拉维酸 ,其在不同 p H条件下的抑制效力差异较大 ,说明克拉维酸的抑酶效力在不同 p H条件下较舒巴坦稳定。但总体上两者在低 p H条件下的抑酶效力均低于高 p H时。另外 ,从时间进程上看 ,舒巴坦和克拉维酸的抑制作用具有时间依赖性 ,酶与抑制剂预先行短时间孵育能增强抑制效力 ,但进一步延长孵育时间反而可使抑制效力降低。对以上酶抑制剂的 p H依赖性和时间依赖性用反应旁路假说进行了分析讨论。试验结果提示在 β-内酰胺酶的研究开发过程中应充分考虑其以上性质的临床意义。

The effects of p H( 6.0 ,7.0 ,8.0 ) on twoβ- lactamases inhibitors( sulbactam,clavulanic acid) against threeβ- lactamases( TEM- 2 ,SHV- 1,OXA- 3) were measured.The results showed thatthe three β- lactamases were significantly inhibited by clavulanic acid,while the inhibition of sulbactam against OXA- 3 was significantly lower than thatagaist TEM- 2 and SHV- 1.Clavulanic acid was less susceptible to differentp H value than sulbactam. So we think that the inhibition of clavulanic acid againstβ- lactamases at different p H values is more stable than that of sulbactam. In general,both sulbactam and clavulanic acid had poorer inhibitory activities atp H6.0 than at p H8.0 .The results also showed thatthe inhibition ofβ- lactamases by two inhibitors were time dependent.β- lactamases were incubated with inhibitors,the inhibition activity first increased with time but then decreased slightly. The dependence of inhibitors on p H and time were best explained by the hypothesis. The study suggested that attention should be paid to the significance of characteristic ofβ- lactamases inhibitors in clinical trial.