NextGen microbial natural products discovery.
NextGen microbial natural products discovery.
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DOI：
10.1111/1751-7915.12184
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发表时间：
2015-01
影响因子：
5.7
通讯作者：
Schmidt-Dannert C
中科院分区：
文献类型：
--
作者：
Schmidt-Dannert C
从微生物和植物中分离的小分子次级代谢产物为当今大部分药物提供了化学支架。进化的力量塑造了这些天然产物的分子复杂性，这些天然产物有助于这些化合物与生物靶点的精确结合。从弗莱明发现青霉素开始，我们看到天然产物及其衍生物如抗生素和其他药物的发现和生产迅速增加。但是，一旦“容易获得”的生物活性化合物被分离出来，药物发现管道从20世纪90年代开始放缓。制药公司放弃了天然产品，因为筛选方案导致重新发现已知结构，而使用合成方法将结构复杂的天然产品开发成药物，如果没有可靠的生物来源，则证明是具有挑战性的，而且过于昂贵。考虑到迫切需要开发新药以对抗多重耐药病原体并克服长期副作用和/或当前药物有效性的降低，解锁小分子化学多样性的自然宝库对于下一代药物开发将是至关重要的（Gerwick和摩尔，2012; Basmadjian等人，2014; Genilloud，2014）。在测序、基因合成、生物信息学和代谢组学进步的推动下，天然产物发现过程开始经历重大转变-从繁琐的分离、筛选和去复制过程转向基于计算机的生物勘探方法，这些方法寻求最终将基因组信息直接转化为生物合成产物（刘易斯，2013;迪恩和米切尔，2014）。可获得的微生物基因组序列数量的爆炸性增长使我们得以一瞥这些生物体隐藏的天然产物生物合成能力。基于参与合成的酶的已知序列信息，例如生物活性聚酮化合物、非核糖体肽或萜烯的支架，可以在沉默的微生物基因组中鉴定出许多基因簇（真菌）和操纵子（细菌），并且没有鉴定出次级代谢产物。这也包括许多充分研究的天然产物生产者，例如链霉菌和曲霉菌株，其在典型的实验室生长条件下仅表达其次级代谢组的子集（Brakhage，2013; Doroghazi和Metcalf，2013; Lim和Keller，2014;
Small-molecule secondary metabolites isolated from microorganisms and plants provide the chemical scaffolds of a large fraction of today’s pharmaceuticals. Evolutionary forces shaped the molecular complexity of these natural products that contribute to the exquisite binding of these compounds to biological targets. Starting with the discovery of penicillin by Fleming, we have seen a rapid increase in the discovery and production of natural products and derivatives thereof as antibiotics and other drugs. But once the ‘easy to access’ bioactive compounds have been isolated, the drug discovery pipeline slowed down beginning in the 1990s. Pharmaceutical companies turned away from natural products as screening programmes led to the rediscovery of known structures and development of structurally complex natural products into drugs using synthetic methods proved to be challenging and too expensive if no reliable biological sources were available. Considering the urgent need for the development of new drugs to combat multidrug-resistant pathogens and overcome long-term side-effects and/or reduction in effectiveness of current drugs, unlocking nature’s treasure trough of smallmolecule chemodiversity will be crucial for next-generation drug development (Gerwick and Moore, 2012; Basmadjian et al., 2014; Genilloud, 2014). Driven by advances in sequencing, gene synthesis, bioinformatics and metabolomics, the natural products discovery process is beginning to undergo a major transformation–away from the tedious isolation, screening and dereplication process to in silico-based bioprospecting approaches that seek to eventually transform genomic information directly into biosynthetic outputs (Lewis, 2013; Deane and Mitchell, 2014). The explosion in the number of available microbial genome sequences has given us a glance at the hidden natural product biosynthetic capacity of these organisms. Based on known sequence information for enzymes involved in synthesizing, eg the scaffolds of bioactive polyketides, non-ribosomal peptides or terpenes, numerous gene clusters (fungi) and operons (bacteria) can be identified in microbial genomes that are silent and for which no secondary metabolite products have been identified. This also includes many well-studied natural products producers such as Streptomyces and Aspergillus strains that express only a subset of their secondary metabolome under typical laboratory growth conditions (Brakhage, 2013; Doroghazi and Metcalf, 2013; Lim and Keller, 2014;
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影响因子：
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作者：
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