NB2001, a novel antibacterial agent with broad-spectrum activity and enhanced potency against β-lactamase-producing strains
NB2001, a novel antibacterial agent with broad-spectrum activity and enhanced potency against β-lactamase-producing strains
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DOI：
10.1128/aac.46.5.1262-1268.2002
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发表时间：
2002-05-01
影响因子：
4.9
通讯作者：
Chan, MF
中科院分区：
文献类型：
--
作者：
Li, Q;Lee, JY;Chan, MF
酶催化治疗激活（ECTA）是一种克服酶过表达引起的耐药的新型药前策略。β -内酰胺酶过表达是细菌对β -内酰胺类抗生素耐药的常见机制。我们在这里展示了一种β -内酰胺酶ECTA化合物NB2001的结果，NB2001由抗菌药物三氯生和头孢菌素支架组成。与传统的β -内酰胺类抗生素不同，β -内酰胺环水解会使抗生素失活，而β -内酰胺酶水解NB2001会释放三氯生。支持提议机制的证据如下。(i) NB2001是TEM-1 β -内酰胺酶的底物，形成三氯生的二级速率常数（k(cat)/ k -m）大于77,000 M-1 s（-1）。（ii）在nb2001处理过的产生β -内酰胺酶的大肠杆菌中检测到三氯生，但在不表达β -内酰胺酶的大肠杆菌中检测不到。（iii）在β -内酰胺酶抑制剂克拉维酸的存在下，NB2001对产生β -内酰胺酶的大肠杆菌的活性降低。NB2001对临床分离的金黄色葡萄球菌（包括MRSA）、表皮葡萄球菌、肺炎链球菌、耐万古霉素的粪肠球菌、卡他莫拉菌和流感嗜血杆菌的疗效与对照抗生素相似或更强。NB2001对肺炎克雷伯菌、产气肠杆菌和阴沟肠杆菌也有活性。结果表明NB2001是一种有效的广谱抗菌剂，并表明ECTA在克服β -内酰胺酶介导的耐药方面具有潜力。
Enzyme-catalyzed therapeutic activation (ECTA) is a novel prodrug strategy to overcome drug resistance resulting from enzyme overexpression. beta-Lactamase overexpression is a common mechanism of bacterial resistance to beta-lactam antibiotics. We present here the results for one of the beta-lactamase ECTA compounds, NB2001, which consists of the antibacterial agent triclosan in a prodrug form with a cephalosporin scaffold. Unlike conventional beta-lactam antibiotics, where hydrolysis of the beta-lactam ring inactivates the antibiotic, hydrolysis of NB2001 by beta-lactamase releases triclosan. Evidence supporting the proposed mechanism is as follows. (i) NB2001 is a substrate for TEM-1 beta-lactamase, forming triclosan with a second-order rate constant (k(cat)/K-m) of greater than 77,000 M-1 s(-1). (ii) Triclosan is detected in NB2001-treated, beta-lactamase-producing Escherichia coli but not in E. coli that does not express beta-lactamase. (iii) NB2001 activity against beta-lactamase-producing E. coli is decreased in the presence of the beta-lactamase inhibitor clavulanic acid. NB2001 was similar to or more potent than reference antibiotics against clinical isolates of Staphylococcus aureus (including MRSA), Staphylococcus epidermidis', Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis, Moraxella catarrhalis and Haemophilus influenzae. NB2001 is also active against Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. The results indicate that NB2001 is a potent, broad-spectrum antibacterial agent and demonstrate the potential of ECTA in overcoming beta-lactamase-mediated resistance.