加拿大麦克马斯特大学E. D. Brown团队近日取得一项新成果。经过不懈努力，他们的研究开发出了链霉菌巨簇编码协同生物素靶向抗生素。相关论文于2026年6月24日发表在《自然》杂志上。

该课题组表明链霉菌属编码一个高度保守的生物合成巨簇，与生物素结合蛋白链亲和素一起产生结构独特的天然产物家族——链霉素、酸霉素、达帕霉素和2-甲基-7-酮-8-氨基甲酸（α-Me-KAPA）。这些成分通过互补机制汇聚到细菌生物素代谢中，包括酶抑制、前药激活、辅因子模拟和生物素隔离。编码的代谢物在革兰氏阴性菌和分枝杆菌中共同产生并协同作用，在多重耐药大肠杆菌感染的单主题模型中，链霉抗生物素S2和α-Me-KAPA联合使用显示出更强的疗效。这个巨型集群揭示了一种基因编码的化学武器库，它作为一种自然进化的联合疗法，对抗保守的代谢途径。更广泛地说，他们的发现表明，高阶生物合成结构可能代表了一个被忽视的抗生素机制储存库，并支持从发现孤立的天然产物到重建天然协同系统的转变。

据介绍，天然产物仍然是抗生素的主要来源，但传统的发现努力将生物合成基因标记作为个体生物活性分子的来源。越来越多的证据表明，微生物可以编码协调的多代谢物系统，但这些系统的遗传结构和生物逻辑仍然知之甚少。

附：英文原文

Title: A Streptomyces megacluster encodes synergistic biotin-targeting antibiotics

Author: Gordzevich, R., Xu, M., Wang, W., Cook, M. A., Hackenberger, D., Deisinger, J. P., Tu, M. M., Carfrae, L. A., George, M., Rachwalski, K., Koteva, K., Sychantha, D., Wei, A., Wright, G. D., Brown, E. D.

Issue&Volume: 2026-06-24

Abstract: Natural products remain a major source of antibiotics, but discovery efforts have traditionally treated biosynthetic gene clusters as sources of individual bioactive molecules1,2,3,4,5. Increasing evidence has suggested that microorganisms can instead encode coordinated multi-metabolite systems, yet the genetic architectures and biological logic of such systems remain poorly understood6,7,8,9,10,11,12. Here we show that Streptomyces spp. encode a highly conserved biosynthetic megacluster that produces four structurally distinct natural product families—stravidins, acidomycin, dapamycins, and 2-methyl-7-keto-8-aminopelargonic acid (α-Me-KAPA)—alongside the biotin-binding protein streptavidin. These components converge on bacterial biotin metabolism through complementary mechanisms, including enzyme inhibition, prodrug activation, cofactor mimicry and biotin sequestration. The encoded metabolites are co-produced and act synergistically across Gram-negative and mycobacterial species, with stravidin S2 and α-Me-KAPA showing enhanced efficacy in combination in a mouse model of multidrug-resistant Escherichia coli infection. This megacluster reveals a genetically encoded chemical arsenal that functions as a naturally evolved combination therapy against a conserved metabolic pathway. More broadly, our findings suggest that higher-order biosynthetic architectures may represent an overlooked reservoir of antibiotic mechanisms and support a shift from discovering isolated natural products to reconstructing native synergistic systems.

DOI: 10.1038/s41586-026-10647-9

Source: https://www.nature.com/articles/s41586-026-10647-9