Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance.
Prospects for circumventing aminoglycoside kinase mediated antibiotic resistance.
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DOI：
10.3389/fcimb.2013.00022
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发表时间：
2013
影响因子：
5.7
通讯作者：
Berghuis AM
中科院分区：
文献类型：
--
作者：
Shi K;Caldwell SJ;Fong DH;Berghuis AM
氨基糖苷类抗生素是一类具有广谱抗菌活性的抗生素。不幸的是，临床分离株的耐药性普遍存在，使许多氨基糖苷类药物无效。对这类抗生素最广泛传播的耐药方式是氨基糖苷类修饰酶（艾姆斯）使药物失活。有两个主要的策略来克服艾姆斯的影响。第一种方法是设计新的氨基糖苷类，可以逃避修改。尽管这种策略已经产生了许多上级氨基糖苷类变体，但它们的疗效不能长期维持。第二种方法需要开发干扰艾姆斯机制的分子，从而保留氨基糖苷类的活性。虽然这种分子尚未进入临床开发，但近年来积累的丰富结构信息极大地促进了AME抑制剂的研究。特别是，氨基糖苷类磷酸转移酶或激酶（APHs）已被广泛研究，并已阐明了具有不同区域特异性和底物特异性的许多APHs的晶体结构。本文综述了APH结构及其抑制剂的研究进展，重点介绍了结构导向的APH抑制策略。
Aminoglycosides are a class of antibiotics with a broad spectrum of antimicrobial activity. Unfortunately, resistance in clinical isolates is pervasive, rendering many aminoglycosides ineffective. The most widely disseminated means of resistance to this class of antibiotics is inactivation of the drug by aminoglycoside-modifying enzymes (AMEs). There are two principal strategies to overcoming the effects of AMEs. The first approach involves the design of novel aminoglycosides that can evade modification. Although this strategy has yielded a number of superior aminoglycoside variants, their efficacy cannot be sustained in the long term. The second approach entails the development of molecules that interfere with the mechanism of AMEs such that the activity of aminoglycosides is preserved. Although such a molecule has yet to enter clinical development, the search for AME inhibitors has been greatly facilitated by the wealth of structural information amassed in recent years. In particular, aminoglycoside phosphotransferases or kinases (APHs) have been studied extensively and crystal structures of a number of APHs with diverse regiospecificity and substrate specificity have been elucidated. In this review, we present a comprehensive overview of the available APH structures and recent progress in APH inhibitor development, with a focus on the structure-guided strategies.
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影响因子：
--
作者：
Boehr, DD;Lane, WS;Wright, GD
通讯作者：
Wright, GD
影响因子：
3.5
作者：
BECK, E;LUDWIG, G;SCHALLER, H
通讯作者：
SCHALLER, H
DOI：
10.1111/j.1365-2125.1995.tb05719.x
发表时间：
1995-06-01
影响因子：
3.4
作者：
BEGG, EJ;BARCLAY, ML;DUFFULL, SB
通讯作者：
DUFFULL, SB
影响因子：
4.9
作者：
Alangaden, GJ;Kreiswirth, BN;Lerner, SA
通讯作者：
Lerner, SA
DOI：
10.1007/bf00330443
发表时间：
1987-06-01
期刊：
MOLECULAR AND GENERAL GENETICS
影响因子：
--
作者：
DISTLER, J;BRAUN, C;PIEPERSBERG, W
通讯作者：
PIEPERSBERG, W