Origins of Yersinia pestis sensitivity to the arylomycin antibiotics and the inhibition of type I signal peptidase.
Origins of Yersinia pestis sensitivity to the arylomycin antibiotics and the inhibition of type I signal peptidase.
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鼠疫耶尔森氏菌对 arylomycin 抗生素的敏感性和 I 型信号肽酶的抑制的起源。
DOI：
10.1128/aac.00181-15
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发表时间：
2015
影响因子：
4.9
通讯作者：
Romesberg,FloydE
中科院分区：
文献类型：
--
作者：
Steed,DanielleB;Liu,Jian;Wasbrough,Elizabeth;Miller,Lynda;Halasohoris,Stephanie;Miller,Jeremy;Somerville,Brandon;Hershfield,JeremyR;Romesberg,FloydE
鼠疫耶尔森氏菌是鼠疫的病原体。关于鼠疫耶尔森氏菌菌株对目前批准的一线和预防治疗的每一种都具有抗药性的报告表明，迫切需要开发具有抗病原体活性的新型抗生素。我们以前报道过鼠疫耶尔森氏菌KIM6+菌株与大多数肠杆菌科细菌不同，它对芳香菌素敏感，芳霉素类是一种新型的天然产物脂肽抗生素，可以抑制信号肽I(Spase)。在这项研究中，我们证明了芳香霉素的活性对广泛的鼠疫杆菌菌株是保守的，并确认它是由于Spase的抑制而产生的。接下来，我们研究了这种独特的芳香霉素敏感性的来源，发现它并不是由于鼠疫杆菌对抗生素亲和力的增加，而且鼠疫菌脂多糖-O抗原、核心和类脂A-的每个成分的改变至多只有很小的贡献。相反，这种敏感性的起源可以追溯到对Spase活性的依赖增加，这是生理条件下高水平蛋白质分泌的结果。这些结果突显了在严重依赖这一过程的情况下靶向蛋白质分泌的潜力，并对芳香菌素作为抗生素的开发具有抗鼠疫杆菌和潜在的其他革兰氏阴性病原体的活性也有影响。
Yersinia pestis is the etiologic agent of the plague. Reports of Y. pestis strains that are resistant to each of the currently approved first-line and prophylactic treatments point to the urgent need to develop novel antibiotics with activity against the pathogen. We previously reported that Y. pestis strain KIM6+, unlike most Enterobacteriaceae, is susceptible to the arylomycins, a novel class of natural-product lipopeptide antibiotics that inhibit signal peptidase I (SPase). In this study, we show that the arylomycin activity is conserved against a broad range of Y. pestis strains and confirm that it results from the inhibition of SPase. We next investigated the origins of this unique arylomycin sensitivity and found that it does not result from an increased affinity of the Y. pestis SPase for the antibiotic and that alterations to each component of the Y. pestis lipopolysaccharide—O antigen, core, and lipid A—make at most only a small contribution. Instead, the origins of the sensitivity can be traced to an increased dependence on SPase activity that results from high levels of protein secretion under physiological conditions. These results highlight the potential of targeting protein secretion in cases where there is a heavy reliance on this process and also have implications for the development of the arylomycins as an antibiotic with activity against Y. pestis and potentially other Gram-negative pathogens.