Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, NY 10065, USA.
Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ 07110, USA.
Science. 2022 May 27;376(6596):991-996. doi: 10.1126/science.abn4213. Epub 2022 May 26.
Emerging resistance to currently used antibiotics is a global public health crisis. Because most of the biosynthetic capacity within the bacterial kingdom has remained silent in previous antibiotic discovery efforts, uncharacterized biosynthetic gene clusters found in bacterial genome-sequencing studies remain an appealing source of antibiotics with distinctive modes of action. Here, we report the discovery of a naturally inspired lipopeptide antibiotic called cilagicin, which we chemically synthesized on the basis of a detailed bioinformatic analysis of the biosynthetic gene cluster. Cilagicin's ability to sequester two distinct, indispensable undecaprenyl phosphates used in cell wall biosynthesis, together with the absence of detectable resistance in laboratory tests and among multidrug-resistant clinical isolates, makes it an appealing candidate for combating antibiotic-resistant pathogens.
目前使用的抗生素出现耐药性是全球公共健康危机。由于在以前的抗生素发现工作中，细菌王国的大多数生物合成能力一直处于沉默状态，因此在细菌基因组测序研究中发现的未被描述的生物合成基因簇仍然是具有独特作用模式的抗生素的有吸引力的来源。在这里，我们报告了一种天然灵感的脂肽抗生素的发现，称为西拉菌素，我们根据生物合成基因簇的详细生物信息学分析对其进行了化学合成。西拉菌素能够螯合两种不同的、不可缺少的十一碳烯磷酸，用于细胞壁生物合成，并且在实验室测试中和多药耐药临床分离株中均未检测到耐药性，这使其成为对抗抗药性病原体的有吸引力的候选药物。
