LOSS OF INDIVIDUAL ELECTROSTATIC INTERACTIONS BETWEEN AMINOGLYCOSIDE ANTIBIOTICS AND RESISTANCE ENZYMES AS AN EFFECTIVE MEANS TO OVERCOMING BACTERIAL DRUG RESISTANCE
LOSS OF INDIVIDUAL ELECTROSTATIC INTERACTIONS BETWEEN AMINOGLYCOSIDE ANTIBIOTICS AND RESISTANCE ENZYMES AS AN EFFECTIVE MEANS TO OVERCOMING BACTERIAL DRUG RESISTANCE
复制标题
氨基糖苷类抗生素与耐药酶之间个体静电相互作用的丧失是克服细菌耐药性的有效手段
DOI：
10.1021/ja00150a004
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发表时间：
1995
影响因子：
15
通讯作者：
S. Mobashery
中科院分区：
文献类型：
--
作者：
J. Roestamadji;I. Grapsas;S. Mobashery
氨基糖苷类修饰酶修饰氨基糖苷类抗生素的结构，使其无效，这一过程赋予抗生素耐药性。静电相互作用（离子配对和氢键）被认为是重要的底物识别和催化这些酶。描述了新霉胺和卡那霉素A两种氨基糖苷类抗生素的七种不同的脱氨基类似物的区域特异性合成。这些化合物中的每一种都将与酶活性位点的不同亚位点具有受损的相互作用。所有七种分子均显示为两种氨基糖苷类修饰酶（氨基糖苷类3 '-磷酸转移酶Ia型和Ha型）的极差底物。活性中心功能与这些胺中的每一个的相互作用对过渡态物种的稳定化的能量贡献已被评估为在6-11 kcal/mol的范围内，这种相互作用的文献中记录的最大能量贡献。这些类似物对携带Ia和Ha型氨基糖苷类3 '-磷酸转移酶的耐药微生物的生物活性与对不含耐药酶的背景菌株的生物活性相同。因此，这些化合物在体内几乎不被这些酶修饰。这里描述的原则应该是普遍感兴趣的规避耐药性的其他抗生素，通过重新设计的结构，以尽量减少静电相互作用与其相应的耐药enzymes.Advances在开发新的抗生素被逆转的细菌种群表现出多重耐药性的各种抗生素。耐药性问题已经使许多抗生素过时。由这种耐药生物体引起的临床感染的治疗提出了严重的挑战。1这种现象需要深入研究具有新作用机制的新抗生素。这些工作既费时又费钱，但如果我们要在不久的将来提供可接受的护理服务，这些工作仍然是不可或缺的。同时，采用策略规避现有的细菌耐药性机制，从而恢复已被耐药性损害的抗菌药物的有效性，可能在时间和金钱上花费不多。氨基糖苷类抗生素已在临床上使用了近五十年。这种长期的临床使用导致了对这一系列抗菌剂的有效选择。目前，对这些药剂的耐药性在全世界的病原体中广泛存在。2氨基糖苷类抗生素耐药的主要机制是细菌获得了通过乙酰转移酶、腺苷酰转移酶和磷酸转移酶活性修饰该家族抗生素的酶。2在这些酶家族中，氨基糖苷3 '-磷酸转移酶[APH（3'）s]具有广泛代表性，其中已知7种同工酶。2这些酶催化ATP的y-磷酰基转移到许多氨基糖苷类的3 '-羟基，如卡那霉素、新霉素、新霉胺、巴龙胺、布替罗新、核糖霉素、利维多霉素、庆大霉素
Aminoglycoside-modifying enzymes modify the structures of aminoglycoside antibiotics, rendering them ineffective, a process which confersresistance to the antibiotic. Electrostatic interactions (ion pairing and hydrogen bonding) are believed to be significant for both substrate recognition and catalysis by these enzymes. Regiospecific syntheses of seven distinct deaminated analogues of neamine and kanamycin A, two aminoglycoside antibiotics, are described. Each of these compounds would have impaired interaction with a different subsite of the enzyme active sites. All seven molecules were shown to be exceedingly poor substrates for two aminoglycoside-modifying enzymes, aminoglycoside 3'-phosphotransferases types la and Ha. The energetic contribution of interactions of the active-site functions with each of these amines on stabilization of the transition-state specieshas been evaluated to be in the range of 6—11 kcaVmol, the largest energy contribution recorded in the literature for such interactions. The biological activities of these analogues were the same against the resistant organisms harboring aminoglycoside 3'-phosphotransferases types la and Ha as those against the background strain without the resistant enzymes. Thus, these compounds are virtually unmodified by those enzymes in vivo. The principles described here should be of general interest for circumvention of resistance to other antibiotics, by redesigning the structures to minimize electrostatic interactions with their corresponding resistance enzymes.Advances in the development of novel antibiotics are being reversed by bacterial populations exhibiting multiple resistance to various antibiotics. The resistance problem has rendered a number of antibiotics obsolete. Treatment of clinical infections caused by such resistant organisms presents a serious challenge. 1 This phenomenon necessitates an intensive search for new antibiotics with novel mechanisms of action. Such undertakings are both time-consuming and financially prohibitive but remain indispensable if we are to provide an acceptable level of care in the immediate future. Meanwhile, it may beless costly in time and money to employ strategiesto circumvent existing bacterial resistance mechanisms and thereby to restore usefulness to antibacterials that have become compromised by resistance. Aminoglycoside antibiotics have been used in the clinic for almost five decades. This prolonged clinical use has resulted in effective selection of resistance to this family of antibacterial agents. Presently, resistance to these agents is widespread among pathogens worldwide. 2 The primary mechanism for resistance to aminoglycosides is the bacterial acquisition of enzymes which modify this family of antibiotics by acetyltrans-ferase, adenylyltransferase, and phosphotransferase activities. 2 Among these enzyme families, aminoglycoside 3'-phosphotransferases [APH (3') s], of which seven isozymes are known, are widely represented. 2 These enzymes catalyze transfer of the y-phosphoryl group of ATP to the 3'-hydroxyl of many aminoglycosides, such as kanamycins, neomycins, neamine, paromamine, butirosin, ribostamycin, lividomycin, gentamicin