Crystal structures of a bioactive 6'-hydroxy variant of sisomicin bound to the bacterial and protozoal ribosomal decoding sites
Crystal structures of a bioactive 6'-hydroxy variant of sisomicin bound to the bacterial and protozoal ribosomal decoding sites
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与细菌和原生动物核糖体解码位点结合的西索米星生物活性 6-羟基变体的晶体结构
DOI：
10.1002/cmdc.201200579
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发表时间：
2013
期刊：
影响因子：
3.4
通讯作者：
Stephen Hanessian
中科院分区：
文献类型：
--
作者：
Jiro Kondo;Mai Koganei;Juan Pablo Maianti,Vu Linh Ly;Stephen Hanessian
寄生虫感染被认为是被忽视的热带疾病，是世界若干区域关切的一个问题。氨基糖苷类抗生素是一种有效的抗菌药物，在原核生物中已被广泛研究。然而，其潜在的抗原生动物活性的分子机制还不太清楚。在本研究中，我们已经检查了一些在环I上具有6′-羟基的氨基糖苷类的体外抑制活性，并强调其中之一，6′-羟基西索米星，对广泛的原生动物寄生虫表现出有希望的活性。 此外，我们还对与靶核糖体RNA A位点结合的6′-羟基西索米星进行了X射线分析，以了解其在分子水平上的抗菌和抗原生动物活性机制。6′-羟基西索米星的不饱和环I可以通过π-π相互作用直接堆叠在细菌和原生动物物种中高度保守的G1491上，并且比其他结构相关的氨基糖苷类的典型饱和和羟基化环I更接近胍基。 因此，该化合物在细菌和原生动物的A位点内采用较低能量的构象，并在位置1408处与A或G形成假对。 A位点选择性结合模式强烈表明，6′-羟基西索米星是设计针对各种感染性疾病的下一代氨基糖苷类药物的潜在先导。
Parasitic infections recognized as neglected tropical diseases are a source of concern for several regions of the world. Aminoglycosides are potent antimicrobial agents that have been extensively studied by biochemical and structural studies in prokaryotes. However, the molecular mechanism of their potential antiprotozoal activity is less well understood. In the present study, we have examined the in vitro inhibitory activities of some aminoglycosides with a 6′‐hydroxy group on ring I and highlight that one of them, 6′‐hydroxysisomicin, exhibits promising activity against a broad range of protozoan parasites. Furthermore, we have conducted X‐ray analyses of 6′‐hydroxysisomicin bound to the target ribosomal RNA A‐sites in order to understand the mechanisms of both its antibacterial and antiprotozoal activities at the molecular level. The unsaturated ring I of 6′‐hydroxysisomicin can directly stack on G1491, which is highly conserved in bacterial and protozoal species, through π–π interaction and fits closer to the guanidine base than the typically saturated and hydroxylated ring I of other structurally related aminoglycosides. Consequently, the compound adopts a lower energy conformation within the bacterial and protozoal A‐sites and makes pseudo pairs to either A or G at position 1408. The A‐site‐selective binding mode strongly suggests that 6′‐hydroxysisomicin is a potential lead for the design of next‐generation aminoglycosides targeting a wide variety of infectious diseases.