Inhibitors of Metallo--lactamase Generated from src="http://pubs.acs.org/images/gifchars/beta2.gif" border="0" a

详细信息    查看全文

• 作者：Adriana Badarau ; Antonio Llin&aacute ; s ; Andrew P. Laws ; Christian Damblon ; and Michael I. Page
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：June 21, 2005
• 年：2005
• 卷：44
• 期：24
• 页码：8578 - 8589
• 全文大小：225K
• 年卷期：v.44,no.24(June 21, 2005)
• ISSN：1520-4995

文摘

The resistance of bacteria to the normally lethal action of s/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lactam antibiotics is largely dueto the production of s/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lactamases that catalyze the hydrolysis of the s/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lactam. One class of these enzymesis a zinc-dependent metallo-s/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lactamase for which there are no clinically available inhibitors. The hydrolysisof cephalosporin s/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lactam antibiotics generates dihydrothiazines which subsequently undergo isomerizationat C6 by C-S bond cleavage and through the intermediacy of a thiol. These thiols can be trapped by thes/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lactamase from Bacillus cereus, causing inhibition of the enzyme. The rate of production of the thiolcorresponds to the rate of inhibition, and the inhibition constants are in the micromolar range but varywith the nature of the cephalosporin derivative. NMR studies have identified the structure of the thiolscausing inhibition and also show that the thiol binds to the zinc ion, which in turn perturbs the metal-bound histidines. Inhibition is slowly removed as the thiol becomes oxidized or undergoes furtherdegradation. The thiol intermediate generated from cephalothin is a slow binding inhibitor. There is noobserved inhibition from the analogous degradation products from penicillins.