科学家开发出一种针对多重耐药病原体的天然抗生素
2022-01-09   阅读:658   来源:自然

美国洛克菲勒大学Sean F. Brady研究团队开发出一种针对多重耐药病原体的天然抗生素。该研究于2022年1月5日在线发表于国际一流学术期刊《自然》。

研究人员表示,革兰氏阴性菌是造成越来越多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对付一些革兰氏阴性病原体的最后一道防线。最近,质粒携带的移动型大肠杆菌素抗性基因mcr-1(磷酸乙醇胺转移酶)在全球蔓延,威胁到大肠杆菌素的效用。细菌衍生的抗生素在自然界中经常以类似结构的集合出现,这些结构是由进化相关的生物合成基因簇编码的。这种结构的多样性,至少在某种程度上,预计是对自然抗性发展的反应,而自然抗性往往在机理上模仿了临床抗性。
 
研究人员提出,解决mcr-1介导的耐药性的方法可能已经在自然发生的粘菌素同系物中进化。对已测序的细菌基因组进行的生物信息学分析确定了一个生物合成基因簇,该基因簇被预测为编码一种结构不同的粘菌素同系物。这种结构的化学合成产生了macolacin,它对表达mcr-1的革兰氏阴性病原体和编码磷酸乙醇胺转移酶基因的抗性病原体有活性。这些革兰氏阴性细菌包括广泛耐药的鲍曼不动杆菌和本质上耐粘菌素的淋病奈瑟菌,由于缺乏有效的治疗方案,这些细菌被认为是最高级别的威胁病原体之一。在小鼠中性粒细胞感染模型中,macolacin的联苯类似物被证明对具有大肠杆菌耐药性的鲍曼不动杆菌有效,从而为克服大肠杆菌耐药性的病原体提供了一个自然启发和易于生产的治疗线索。
 
附:英文原文
 
Title: A naturally inspired antibiotic to target multidrug-resistant pathogens

Author: Wang, Zongqiang, Koirala, Bimal, Hernandez, Yozen, Zimmerman, Matthew, Park, Steven, Perlin, David S., Brady, Sean F.

Issue&Volume: 2022-01-05

Abstract: Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections1,2. The bacterial natural product colistin is considered the last line of defence against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin-resistance gene mcr-1 (phosphoethanolamine transferase) threatens the usefulness of colistin3. Bacteria-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters. This structural diversity is, at least in part, expected to be a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here we propose that a solution to mcr-1-mediated resistance might have evolved among naturally occurring colistin congeners. Bioinformatic analysis of sequenced bacterial genomes identified a biosynthetic gene cluster that was predicted to encode a structurally divergent colistin congener. Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens expressing mcr-1 and intrinsically resistant pathogens with chromosomally encoded phosphoethanolamine transferase genes. These Gram-negative bacteria include extensively drug-resistant Acinetobacter baumannii and intrinsically colistin-resistant Neisseria gonorrhoeae, which, owing to a lack of effective treatment options, are considered among the highest level threat pathogens4. In a mouse neutropenic infection model, a biphenyl analogue of macolacin proved to be effective against extensively drug-resistant A. baumannii with colistin-resistance, thus providing a naturally inspired and easily produced therapeutic lead for overcoming colistin-resistant pathogens.

DOI: 10.1038/s41586-021-04264-x

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