Protein kinase inhibitors and antibiotic resistance
Protein kinase inhibitors and antibiotic resistance
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DOI：
10.1016/s0163-7258(02)00197-3
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发表时间：
2002-02-01
影响因子：
13.5
通讯作者：
Berghuis, AM
中科院分区：
文献类型：
--
作者：
Burk, DL;Berghuis, AM
虽然抗生素在20世纪彻底改变了传染病的治疗，但细菌耐药性现在可能使许多抗生素无效。氨基糖苷类是临床上重要的抗生素，用于治疗革兰氏阳性和阴性生物体引起的感染。它们具有杀菌作用，靶向细菌核糖体，在那里它们与a位点结合并破坏蛋白质合成。这些药物的临床耐药主要是由于氨基糖苷修饰酶使氨基糖苷磷酸化、腺苷化或乙酰化而使酶失活。那些磷酸化（即氨基糖苷激酶）已被证明在结构上与真核蛋白激酶相关，这是令人惊讶的，因为酶群之间的序列相似性很低。具体来说，核苷酸结合位点在结构上非常相似，这表明这两类酶具有共同的磷酸化酰基转移机制。可以设想三种策略来对抗氨基糖苷激酶介导的细菌耐药性。第一种是针对抗生素结合区域的化合物。其次，已经发现蛋白激酶抑制剂通过靶向atp结合位点使氨基糖苷修饰酶失活。最后，正在开发的化合物利用活性位点的桥接性质，结合核苷酸和底物基序。使用双功能氨基糖苷二聚体的策略也被追求，产生与细菌核糖体上目标位点结合的分子，同时作为修饰酶的不良底物。这项工作表明，氨基糖苷修饰酶的有效抑制剂可能最终恢复氨基糖苷类抗生素的有效性。(C) 2002爱思唯尔科学有限公司版权所有。
While antibiotics revolutionized the treatment of infectious disease in the 20th century, bacterial resistance now threatens to render many of them ineffective. Aminoglycosides are a class of clinically important antibiotics used in the treatment of infections caused by Gram-positive and -negative organisms, They are bactericidal, targeting the bacterial ribosome, where they bind to the A-site and disrupt protein synthesis. Clinical resistance to these drugs occurs mainly via enzymatic inactivation by ammoglycoside-modifying enzymes that phosphorylate, adenylate, or acetylate the aminoglycoside. Those that phosphorylate (i.e., aminoglycoside kinases) have been shown to be structurally related to eukaryotic protein kinases, This was surprising, given the low degree of sequence similarity between the groups of enzymes. The nucleotide-binding site, specifically, is very similar in structure, suggesting that the two classes of enzymes share a common mechanism of phosphoryl transfer. Three strategies can be envisaged for combating aminoglycoside kinase-mediated bacterial resistance. The first involves compounds that target the antibiotic binding region. Secondly, protein kinase inhibitors have been identified that disable aminoglycoside-modifying enzymes by targeting the ATP-binding site. Lastly, compounds are being developed that exploit the bridged nature of the active site, incorporating nucleotide and substrate motifs. A strategy using bifunctional aminoglycoside dimers has also been pursued, yielding molecules that bind to the target site on the bacterial ribosome, while serving as poor substrates for modifying enzymes. This work holds out the promise that effective inhibitors of aminoglycoside-modifying enzymes may eventually restore the usefulness of aminoglycoside antibiotics. (C) 2002 Elsevier Science Inc. All rights reserved.