M. G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Department of Chemistry, Indiana University, Bloomington, IN, USA.
Nature. 2020 Feb;578(7796):582-587. doi: 10.1038/s41586-020-1990-9. Epub 2020 Feb 12.
Addressing the ongoing antibiotic crisis requires the discovery of compounds with novel mechanisms of action that are capable of treating drug-resistant infections. Many antibiotics are sourced from specialized metabolites produced by bacteria, particularly those of the Actinomycetes family. Although actinomycete extracts have traditionally been screened using activity-based platforms, this approach has become unfavourable owing to the frequent rediscovery of known compounds. Genome sequencing of actinomycetes reveals an untapped reservoir of biosynthetic gene clusters, but prioritization is required to predict which gene clusters may yield promising new chemical matter. Here we make use of the phylogeny of biosynthetic genes along with the lack of known resistance determinants to predict divergent members of the glycopeptide family of antibiotics that are likely to possess new biological activities. Using these predictions, we uncovered two members of a new functional class of glycopeptide antibiotics-the known glycopeptide antibiotic complestatin and a newly discovered compound we call corbomycin-that have a novel mode of action. We show that by binding to peptidoglycan, complestatin and corbomycin block the action of autolysins-essential peptidoglycan hydrolases that are required for remodelling of the cell wall during growth. Corbomycin and complestatin have low levels of resistance development and are effective in reducing bacterial burden in a mouse model of skin MRSA infection.
解决当前的抗生素危机需要发现具有新型作用机制的化合物，这些化合物能够治疗耐药性感染。许多抗生素来源于细菌产生的特殊代谢产物，特别是放线菌家族的抗生素。尽管放线菌提取物传统上是使用基于活性的平台进行筛选，但由于经常重新发现已知化合物，这种方法变得不利。放线菌的基因组测序揭示了生物合成基因簇的未开发资源，但需要进行优先级排序，以预测哪些基因簇可能产生有前途的新化学物质。在这里，我们利用生物合成基因的系统发育以及缺乏已知抗性决定因素，来预测糖肽类抗生素家族中可能具有新生物活性的趋异成员。利用这些预测，我们发现了两种新型糖肽抗生素的新功能类别成员——已知的糖肽抗生素 complestatin 和我们称为 corbomycin 的新发现化合物——它们具有新型作用模式。我们表明，通过与肽聚糖结合，complestatin 和 corbomycin 阻断自溶素的作用——自溶素是必需的肽聚糖水解酶，对于细胞壁在生长过程中的重塑是必需的。corbomycin 和 complestatin 的耐药性发展水平较低，并且在减轻 MRSA 感染小鼠模型中的细菌负担方面非常有效。
