Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark.
mSystems. 2023 Apr 27;8(2):e0072422. doi: 10.1128/msystems.00724-22. Epub 2023 Feb 15.
In the search for novel drug candidates, diverse environmental microbiomes have been surveyed for their secondary metabolite biosynthesis potential, yet little is known about the biosynthetic diversity encoded by divergent microbiomes from different ecosystems, and the environmental parameters driving this diversity. Here, we used targeted amplicon sequencing of adenylation (AD) and ketosynthase (KS) domains along with 16S sequencing to delineate the unique biosynthetic potential of microbiomes from three separate habitats (soil, water, and sediments) exhibiting unique small spatial scale physicochemical gradients. The estimated richness of AD domains was highest in marine sediments with 656 ± 58 operational biosynthetic units (OBUs), while the KS domain richness was highest in soil microbiomes with 388 ± 67 OBUs. Microbiomes with rich and diverse bacterial communities displayed the highest PK potential across all ecosystems, and on a small spatial scale, pH and salinity were significantly, positively correlated to KS domain richness in soil and aquatic systems, respectively. Integrating our findings, we were able to predict the KS domain richness with a RMSE of 31 OBUs and a of 0.91, and by the use of publicly available information on bacterial richness and diversity, we identified grassland biomes as being particularly promising sites for the discovery of novel polyketides. Furthermore, a focus on acidobacterial taxa is likely to be fruitful, as these were responsible for most of the variation in biosynthetic diversity. Overall, our results highlight the importance of sampling diverse environments with high taxonomic diversity in the pursuit for novel secondary metabolites. To counteract the antibiotic resistance crisis, novel anti-infective agents need to be discovered and brought to market. Microbial secondary metabolites have been important sources of inspiration for small-molecule therapeutics. However, the isolation of novel antibiotics is difficult, and the risk of rediscovery is high. With the overarching purpose of identifying promising microbiomes for discovery of novel bioactivity, we mapped out the most significant drivers of biosynthetic diversity across divergent microbiomes. We found the biosynthetic potential to be unique to individual ecosystems, and to depend on bacterial taxonomic diversity. Within systems, and on small spatial scales, pH and salinity correlated positively to the biosynthetic richness of the microbiomes, Acidobacteria representing the taxa most highly associated with biosynthetic diversity. Ultimately, understanding the key drivers of the biosynthesis potential of environmental microbiomes will allow us to focus bioprospecting efforts and facilitate the discovery of novel therapeutics.
在寻找新的药物候选物时，人们已经对各种环境微生物组进行了调查，以了解它们的次生代谢物生物合成潜力，但对于来自不同生态系统的不同微生物组所编码的生物合成多样性以及驱动这种多样性的环境参数知之甚少。在这里，我们使用靶向扩增子测序方法，对来自三个不同生境（土壤、水和沉积物）的微生物组中的腺苷酸化（AD）和酮合酶（KS）结构域进行了测序，并结合 16S 测序，以描绘出具有独特小空间尺度物理化学梯度的微生物组的独特生物合成潜力。海洋沉积物中 AD 结构域的估计丰富度最高，有 656±58 个操作生物合成单元（OBU），而土壤微生物组中 KS 结构域的丰富度最高，有 388±67 个 OBU。具有丰富多样的细菌群落的微生物组在所有生态系统中表现出最高的 PK 潜力，并且在小空间尺度上，土壤和水生系统中的 pH 和盐度与 KS 结构域的丰富度呈显著正相关。综合我们的发现，我们能够以 RMSE 为 31 OBU 和 的 0.91 预测 KS 结构域的丰富度，并且通过使用细菌丰富度和多样性的公开信息，我们确定了草原生物群落是发现新型聚酮类化合物的特别有希望的地点。此外，关注酸杆菌类群可能是富有成效的，因为它们是生物合成多样性变化的主要原因。总的来说，我们的研究结果强调了在追求新型次生代谢物时，对具有高分类多样性的不同环境进行采样的重要性。为了应对抗生素耐药性危机，需要发现和推向市场新型抗感染药物。微生物次生代谢物一直是小分子治疗药物的重要灵感来源。然而，新型抗生素的分离很困难，重发现的风险很高。为了确定有希望发现新型生物活性的微生物组，我们确定了影响不同微生物组生物合成多样性的最重要驱动因素。我们发现，生物合成潜力是各个生态系统所特有的，并且取决于细菌的分类多样性。在系统内和小空间尺度上，pH 和盐度与微生物组的生物合成丰富度呈正相关，酸杆菌类群代表与生物合成多样性高度相关的分类群。最终，了解环境微生物组生物合成潜力的关键驱动因素将使我们能够集中生物勘探工作并促进新型治疗药物的发现。
