Large-Scale Bioinformatics Analysis of Bacillus Genomes Uncovers Conserved Roles of Natural Products in Bacterial Physiology.
Large-Scale Bioinformatics Analysis of Bacillus Genomes Uncovers Conserved Roles of Natural Products in Bacterial Physiology.
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DOI：
10.1128/msystems.00040-17
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发表时间：
2017-11
期刊：
影响因子：
6.4
通讯作者：
Bowers AA
中科院分区：
文献类型：
--
作者：
Grubbs KJ;Bleich RM;Santa Maria KC;Allen SE;Farag S;AgBiome Team;Shank EA;Bowers AA
杆菌能够产生多种专门的代谢物，其中许多代谢物因其作为影响细菌生理和发育的信号而受到关注。然而，到目前为止，芽孢杆菌属的代谢能力尚未得到充分研究。我们对 1,566 个芽孢杆菌基因组进行了深入的基因组分析，以了解该细菌群可以产生的全部代谢物。我们发现芽孢杆菌产生的大多数特殊代谢物都是高度保守的已知化合物，在该细菌的生理和发育中具有重要的信号传导作用。此外，该属中分布着重要的独特生物合成机制，可能会产生具有不同生物功能的新的未知代谢物。受基因组分析结果的启发，我们推测高度保守的烷基吡喃酮可能在该属中具有重要的生物活性。我们通过证明这些天然产物是芽孢杆菌的发育信号并通过抑制孢子形成起作用来继续验证这一预测。细菌具有合成各种结构复杂、具有生物活性的天然产物（称为专门（或次级）代谢物）的惊人能力。许多这些专门的代谢物被用作临床治疗药物，而其他代谢物则在微生物群落中具有重要的生态作用。产生这些代谢物的生物合成基因簇 (BGC) 可以利用其高度保守的遗传特征在细菌基因组序列中进行识别。我们前所未有地分析了芽孢杆菌属的 1,566 个细菌基因组，并鉴定了近 20,000 个 BGC。通过将这些 BGC 以及一组已知的专门代谢物 BGC 进行比较，我们发现大多数芽孢杆菌天然产物由一小组高度保守、分布均匀的已知天然产物化合物组成。大多数这些代谢物对芽孢杆菌属物种的生理和发育具有重要影响。除了这些特征化合物之外，我们还发现了许多独特的、弱保守的 BGC 分散在该属中，预计它们会编码未知的天然产物。许多这些“单一”BGC 似乎是通过水平基因转移获得的。基于芽孢杆菌中代谢物产生的大规模表征，我们继续将烷基吡喃酮（高度保守但以前在生物学上未表征的天然产物）与芽孢杆菌生理学中的作用联系起来：抑制孢子发育。重要性 杆菌能够产生多种专门的代谢物，其中许多代谢物因其作为影响细菌生理和发育的信号而受到关注。然而，到目前为止，芽孢杆菌属的代谢能力尚未得到充分研究。我们对 1,566 个芽孢杆菌基因组进行了深入的基因组分析，以了解该细菌群可以产生的全部代谢物。我们发现芽孢杆菌产生的大多数特殊代谢物都是高度保守的已知化合物，在该细菌的生理和发育中具有重要的信号传导作用。此外，该属中分布着重要的独特生物合成机制，可能会产生具有不同生物功能的新的未知代谢物。受基因组分析结果的启发，我们推测高度保守的烷基吡喃酮可能在该属中具有重要的生物活性。我们通过证明这些天然产物是芽孢杆菌的发育信号并通过抑制孢子形成起作用来继续验证这一预测。
Bacilli are capable of producing a diverse array of specialized metabolites, many of which have gained attention for their roles as signals that affect bacterial physiology and development. Up to this point, however, the Bacillus genus’s metabolic capacity has been underexplored. We undertook a deep genomic analysis of 1,566 Bacillus genomes to understand the full spectrum of metabolites that this bacterial group can make. We discovered that the majority of the specialized metabolites produced by Bacillus species are highly conserved, known compounds with important signaling roles in the physiology and development of this bacterium. Additionally, there is significant unique biosynthetic machinery distributed across the genus that might lead to new, unknown metabolites with diverse biological functions. Inspired by the findings of our genomic analysis, we speculate that the highly conserved alkylpyrones might have an important biological activity within this genus. We go on to validate this prediction by demonstrating that these natural products are developmental signals in Bacillus and act by inhibiting sporulation. Bacteria possess an amazing capacity to synthesize a diverse range of structurally complex, bioactive natural products known as specialized (or secondary) metabolites. Many of these specialized metabolites are used as clinical therapeutics, while others have important ecological roles in microbial communities. The biosynthetic gene clusters (BGCs) that generate these metabolites can be identified in bacterial genome sequences using their highly conserved genetic features. We analyzed an unprecedented 1,566 bacterial genomes from Bacillus species and identified nearly 20,000 BGCs. By comparing these BGCs to one another as well as a curated set of known specialized metabolite BGCs, we discovered that the majority of Bacillus natural products are comprised of a small set of highly conserved, well-distributed, known natural product compounds. Most of these metabolites have important roles influencing the physiology and development of Bacillus species. We identified, in addition to these characterized compounds, many unique, weakly conserved BGCs scattered across the genus that are predicted to encode unknown natural products. Many of these “singleton” BGCs appear to have been acquired via horizontal gene transfer. Based on this large-scale characterization of metabolite production in the Bacilli, we go on to connect the alkylpyrones, natural products that are highly conserved but previously biologically uncharacterized, to a role in Bacillus physiology: inhibiting spore development. IMPORTANCE Bacilli are capable of producing a diverse array of specialized metabolites, many of which have gained attention for their roles as signals that affect bacterial physiology and development. Up to this point, however, the Bacillus genus’s metabolic capacity has been underexplored. We undertook a deep genomic analysis of 1,566 Bacillus genomes to understand the full spectrum of metabolites that this bacterial group can make. We discovered that the majority of the specialized metabolites produced by Bacillus species are highly conserved, known compounds with important signaling roles in the physiology and development of this bacterium. Additionally, there is significant unique biosynthetic machinery distributed across the genus that might lead to new, unknown metabolites with diverse biological functions. Inspired by the findings of our genomic analysis, we speculate that the highly conserved alkylpyrones might have an important biological activity within this genus. We go on to validate this prediction by demonstrating that these natural products are developmental signals in Bacillus and act by inhibiting sporulation.