A naturally inspired antibiotic to target multidrug-resistant pathogens.
A naturally inspired antibiotic to target multidrug-resistant pathogens.
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一种针对多重耐药病原体的天然抗生素。
DOI：
10.1038/s41586-021-04264-x
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发表时间：
2022-01
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
革兰氏阴性菌是导致越来越多的抗生素耐药性感染死亡的原因。细菌天然产物粘菌素被认为是抵抗许多革兰氏阴性病原体的最后一道防线。质粒携带的动员型粘菌素耐药基因mcr-1（磷酸乙醇胺（PEtN）转移酶）最近在全球的传播威胁到粘菌素的效用。细菌衍生的抗生素通常在自然界中作为由进化相关的生物合成基因簇（BGC）编码的相似结构的集合出现。这种结构多样性至少部分可能是对天然耐药性发展的反应，天然耐药性通常在机械上模拟临床耐药性。在这里，我们提出mcr-1介导的耐药性的解决方案可能已经在天然存在的粘菌素同源物中进化出来。我们对测序的细菌基因组的搜索确定了一个BGC，该BGC被预测编码迄今为止描述的结构上最不同的粘菌素同源物。该结构的化学合成产生了macolacin，其对含有mcr-1的革兰氏阴性病原体以及具有染色体编码的PEtN转移酶基因的固有耐药病原体具有活性。这些包括极端耐药（XDR）鲍曼不动杆菌和固有的粘菌素耐药淋球菌，由于缺乏有效的治疗方案，被认为是最高级别的革兰氏阴性威胁。在小鼠血小板减少感染模型中，马可拉辛的联苯类似物被证明对粘菌素抗性XDRA有效。鲍曼不动杆菌，从而提供了一种新的天然启发和容易产生的治疗先导物，用于对抗粘菌素抗性病原体。
Gram-negative bacteria are responsible for an increasing number of deaths from antibiotic resistant infections. The bacterial natural product, colistin, is considered the last line of defense against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin resistance gene mcr-1 (phosphoethanolamine (PEtN) transferase) threatens colistin’s utility. Bacterial-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters (BGCs). This structural diversity is, at least in part, likely a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here, we proposed that a solution to mcr-1 mediated resistance might have evolved among naturally occurring colistin congeners. Our search of sequenced bacterial genomes identified a BGC that was predicted to encode the most structurally divergent colistin congener described to-date. Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens containing mcr-1 as well as intrinsically resistant pathogens with chromosomally encoded PEtN transferase genes. These include extremely drug resistant (XDR) Acinetobacter baumannii and intrinsically colistin resistant Neisseria gonorrhoeae which, due to a lack of effective treatment options, are considered among the highest level Gram-negative threats. In a mouse neutropenic infection model, a biphenyl analog of macolacin proved to be effective against colistin resistant XDR A. baumannii, thus providing a new naturally inspired and easily produced therapeutic lead for combating colistin resistant pathogens.
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影响因子：
4.9
作者：
Lucas, Deanna Deveson;Crane, Bethany;Boyce, John D.
通讯作者：
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影响因子：
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作者：
McClerren, AL;Endsley, S;Raetz, CRH
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Dean, Charles R.
DOI：
10.1590/0037-8682-0237-2019
发表时间：
2019-01-01
影响因子：
2
作者：
Hameed, Fareeha;Khan, Muhammad Asif;Rehman, Tayyab Ur
通讯作者：
Rehman, Tayyab Ur