Genomic and Secondary Metabolite Analyses of Streptomyces sp. 2AW Provide Insight into the Evolution of the Cycloheximide Pathway.
Genomic and Secondary Metabolite Analyses of Streptomyces sp. 2AW Provide Insight into the Evolution of the Cycloheximide Pathway.
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DOI：
10.3389/fmicb.2016.00573
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发表时间：
2016
影响因子：
5.2
通讯作者：
Handelsman J
中科院分区：
文献类型：
--
作者：
Stulberg ER;Lozano GL;Morin JB;Park H;Baraban EG;Mlot C;Heffelfinger C;Phillips GM;Rush JS;Phillips AJ;Broderick NA;Thomas MG;Stabb EV;Handelsman J
面对广泛的抗菌素耐药性，缺乏新的抗生素，这使得开发新抗生素的创新策略对于未来感染性疾病的管理至关重要。了解抗生素生产者的遗传和进化将有助于指导新型抗生素的发现和生物工程。我们在阿拉斯加北部森林土壤中发现了一种具有广泛抗菌活性的菌株。我们阐明了相应的抗菌天然产物，并对该分离物进行了基因组测序，命名为链霉菌2AW。该菌株展示了链霉菌属典型的化学精湛工艺，产生放线菌酮以及其他两种生物合成无关的抗生素，中性霉素和潮霉素A。结合生物信息学和化学分析，我们确定了负责抗生素生产的基因簇。有趣的是，2AW似乎与其他放线菌酮生产者不同，因为编码聚酮合酶的基因位于染色体的一个独立部分，与负责定制放线菌酮特异性修饰的基因不同。这种基因排列和我们的基因产物的系统发育分析表明，2AW持有放线菌酮途径的进化祖先血统。我们的分析支持的假设，2AW戊二酰胺基因簇是基础的谱系，其中放线菌酮生产偏离其他戊二酰亚胺抗生素。这项研究说明了现代生物化学和基因组分析相结合的力量，以深入了解产藻微生物的进化。
The dearth of new antibiotics in the face of widespread antimicrobial resistance makes developing innovative strategies for discovering new antibiotics critical for the future management of infectious disease. Understanding the genetics and evolution of antibiotic producers will help guide the discovery and bioengineering of novel antibiotics. We discovered an isolate in Alaskan boreal forest soil that had broad antimicrobial activity. We elucidated the corresponding antimicrobial natural products and sequenced the genome of this isolate, designated Streptomyces sp. 2AW. This strain illustrates the chemical virtuosity typical of the Streptomyces genus, producing cycloheximide as well as two other biosynthetically unrelated antibiotics, neutramycin, and hygromycin A. Combining bioinformatic and chemical analyses, we identified the gene clusters responsible for antibiotic production. Interestingly, 2AW appears dissimilar from other cycloheximide producers in that the gene encoding the polyketide synthase resides on a separate part of the chromosome from the genes responsible for tailoring cycloheximide-specific modifications. This gene arrangement and our phylogenetic analyses of the gene products suggest that 2AW holds an evolutionarily ancestral lineage of the cycloheximide pathway. Our analyses support the hypothesis that the 2AW glutaramide gene cluster is basal to the lineage wherein cycloheximide production diverged from other glutarimide antibiotics. This study illustrates the power of combining modern biochemical and genomic analyses to gain insight into the evolution of antibiotic-producing microorganisms.