Laboratory of Genetics, University of Wisconsin-Madison, Madison, 53706, WI, USA.
Department of Bacteriology, University of Wisconsin-Madison, Madison, 53706, WI, USA.
Nat Commun. 2019 Jan 31;10(1):516. doi: 10.1038/s41467-019-08438-0.
Antimicrobial resistance is a global health crisis and few novel antimicrobials have been discovered in recent decades. Natural products, particularly from Streptomyces, are the source of most antimicrobials, yet discovery campaigns focusing on Streptomyces from the soil largely rediscover known compounds. Investigation of understudied and symbiotic sources has seen some success, yet no studies have systematically explored microbiomes for antimicrobials. Here we assess the distinct evolutionary lineages of Streptomyces from insect microbiomes as a source of new antimicrobials through large-scale isolations, bioactivity assays, genomics, metabolomics, and in vivo infection models. Insect-associated Streptomyces inhibit antimicrobial-resistant pathogens more than soil Streptomyces. Genomics and metabolomics reveal their diverse biosynthetic capabilities. Further, we describe cyphomycin, a new molecule active against multidrug resistant fungal pathogens. The evolutionary trajectories of Streptomyces from the insect microbiome influence their biosynthetic potential and ability to inhibit resistant pathogens, supporting the promise of this source in augmenting future antimicrobial discovery.
抗微生物药物耐药性是一个全球性的健康危机，近几十年来发现的新型抗微生物药物寥寥无几。天然产物，特别是来自链霉菌的天然产物，是大多数抗微生物药物的来源，但近年来针对土壤中链霉菌的发现活动在很大程度上只是重新发现了已知的化合物。对研究较少的共生来源的研究取得了一些成功，但尚无研究系统地从微生物组中寻找抗微生物药物。在这里，我们通过大规模分离、生物活性测定、基因组学、代谢组学和体内感染模型，评估了昆虫微生物组中的链霉菌作为新型抗微生物药物的来源的独特进化谱系。与土壤中的链霉菌相比，与昆虫相关的链霉菌对抗微生物药物耐药性病原体的抑制作用更强。基因组学和代谢组学揭示了它们多样化的生物合成能力。此外，我们还描述了一种新的抗真菌多药耐药性病原体的分子——环孢菌素。昆虫微生物组中链霉菌的进化轨迹影响其生物合成潜力和抑制耐药病原体的能力，这支持了这一来源在增强未来抗微生物药物发现方面的前景。
