Anti-infective discovery from competitive ecosystems

我们这个时代对全球健康和食品安全的最大威胁之一是抗生素耐药性(AMR)，它导致现有的抗生素对人类和牲畜的治疗变得无效。AMR是一个自然的进化过程，但滥用抗生素(例如，通过不适当的处方)正在导致它以更快的速度发展。为了应对AMR危机，需要发现新的抗生素，其中很大一部分抗生素来自真菌、细菌和植物作为天然产品。这些也被称为次生代谢物(SMS)，是由生物体产生的，因为它们提供了生态和物理优势，以便更好地在它们的栖息地生存。一个相对较少被研究的生物是从切叶蚂蚁中分离出来的丝状真菌Ecovopsis weberi。韦氏杆菌已经适应了在竞争激烈的环境中生长，而短信在其致病能力(致病性)中发挥着关键作用。最近的研究发现，这种真菌产生一系列具有抗真菌和抗菌特性的SM，以与其他微生物竞争。对E.weberi基因组的分析已经证实，这种真菌可以产生许多新的和潜在的生物活性短信。目前，由于缺乏遗传工具和彻底的化学调查，他们的发现受阻。这项研究计划旨在通过开发不同的工具来解决目前的AMR危机，这些工具可以用来发现来自E.weberi的新的天然产品。该项目将使用微生物、化学和基因技术在广泛的生长条件下培养E.weberi，目的是刺激新的SMS的生产。这些培养物将被化学提取，并用一种非常灵敏的技术--液-质联用--进行彻底的研究。任何短信息都将被分离出来，然后进行抗菌和抗真菌活性筛选。在切叶蚂蚁生态系统的背景下，还将调查短信息系统的生态作用。这项研究还将开发第一批基因工具来操纵E.weberi的基因组。这将允许靶向合成新的SM所需的特定基因，在真菌中，新的SM通常排列在被称为多基因生物合成基因簇的地方。基因操作还将致力于设计新的菌株，使其能够大量生产有价值的短信。该项目将是朝着确定新的和有效的抗生素迈出的一步，并进一步证明利用从复杂生态系统中分离的真菌进行天然产品研究的重要性。结果还将使人们更好地了解切叶蚂蚁生态系统，并提供也可以应用于其他微生物群的化学和遗传工具。

One of the biggest threats to global health and food security of our time is antibiotic resistance (AMR) causing existing antibiotics to become ineffective as a treatment for humans and livestock. AMR is a natural evolutionary process but misuse of antibiotics (for example, through inappropriate prescription) is causing it to develop at a much faster rate. In order to tackle the AMR crisis, new antibiotics need to be discovered and a large proportion of antibiotics originate from fungi, bacteria and plants as natural products. These, also called secondary metabolites (SMs), are produced by organisms as they provide an ecological and physical advantage to better survive in their habitat.A relatively understudied organism is the filamentous fungus Escovopsis weberi which has been isolated from leaf-cutter ants. E. weberi has adapted to grow in a very competitive environment, and SMs play a key role in its ability to cause disease (pathogenicity). Recent work has identified that this fungus produces a range of SMs with antifungal and antibacterial properties in order to compete with other microbes. Analysis of the E. weberi genome has identified that this fungus could produce many new and potentially bioactive SMs. At present, their discovery is halted by the lack of genetic tools and thorough chemical investigation. This research program will aim to address the current AMR crisis by developing different tools that can be used to discover new natural products from E. weberi. The project will use microbiological, chemical and genetic techniques to culture E. weberi under a wide range of growth conditions with the aim of stimulating the production of new SMs. These cultures will be chemically extracted and thoroughly investigated with a very sensitive technique called liquid chromatography coupled with mass spectrometry. Any SMs will be isolated and later screened for antibacterial and antifungal activities. The SMs will also be investigated for their ecological role in the context of the leaf-cutter ant ecosystem. The research will also develop the first genetic tools to manipulate the genome of E. weberi. This will allow targeting of specific genes required to synthesise new SMs, which in fungi are usually arranged in what is known as a multigene biosynthetic gene cluster. Genetic manipulation will also aim to engineer new strains that can produce valuable SMs in high quantities. This project will be a step towards identifying new and effective antibiotics and further demonstrate the importance of natural product research using fungi isolated from complex ecosystems. Results will also yield a better understanding of the leaf-cutter ant ecosystem and provide chemical and genetic tools that could also be applied to other microbiomes.