Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-β-Lactamases
Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-β-Lactamases
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DOI：
10.1021/acsinfecdis.7b00129
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发表时间：
2018-03-01
影响因子：
5.3
通讯作者：
Proschak, Ewgenij
中科院分区：
文献类型：
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作者：
Buettner, Dominik;Kramer, Jan S.;Proschak, Ewgenij
表达金属β-内酰胺酶（MBL）的病原体对大多数β-内酰胺抗生素产生耐药性。除了寻找新的抗生素外，MBL抑制剂的开发将是对抗耐药细菌病原体的另一种武器。抑制耐药酶可以恢复β-内酰胺类抗生素的抗菌活性。描述了MBL抑制剂的各种方法;其中，锌配位硫醇部分的有前途的基序是非常受欢迎的。然而，自2001年首次报道基于硫醇的MBL抑制剂（硫代扁桃酸）以来，没有报道基于硫醇的MBL抑制剂的开发步骤超出临床分离株测试。在这项研究中，我们报告了基于巯基的MBL抑制剂的合成和生物化学表征，并强调了基于巯基的化合物开发背后的挑战，这些化合物对广谱MBL表现出良好的体外活性，对人类脱靶的选择性，以及对临床分离株的合理活性。
Pathogens, expressing metallo-beta-lactamases (MBLs), become resistant against most beta-lactam antibiotics. Besides the dragging search for new antibiotics, development of MBL inhibitors would be an alternative weapon against resistant bacterial pathogens. Inhibition of resistance enzymes could restore the antibacterial activity of beta-lactams. Various approaches to MBL inhibitors are described; among others, the promising motif of a zinc coordinating thiol moiety is very popular. Nevertheless, since the first report of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps in development of thiol based MBL inhibitors were reported that go beyond clinical isolate testing. In this study, we report on the synthesis and biochemical characterization of thiol-based MBL inhibitors and highlight the challenges behind the development of thiol-based compounds, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off targets, and reasonable activity against clinical isolates.