Anti-infective discovery from competitive ecosystems

我们这个时代对全球健康和粮食安全的最大威胁之一是抗生素耐药性（AMR），它导致现有抗生素对人类和牲畜的治疗无效。抗生素耐药性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。为了解决抗生素耐药性危机，需要发现新的抗生素，而大部分抗生素作为天然产物来自真菌、细菌和植物。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，以便更好地在其栖息地生存。从切叶蚁中分离到的丝状真菌是一种研究相对较少的生物。weberi已经适应了在竞争激烈的环境中生长，而SMs在其致病能力（致病性）中起着关键作用。最近的工作已经确定，这种真菌产生一系列具有抗真菌和抗菌特性的SMs，以便与其他微生物竞争。通过对该真菌基因组的分析，发现该真菌可以产生许多新的具有潜在生物活性的短体。目前，由于缺乏遗传工具和彻底的化学研究，它们的发现受到阻碍。这项研究计划旨在通过开发不同的工具来发现新的天然产物，以解决当前的抗菌素耐药性危机。该项目将利用微生物学、化学和遗传技术在多种生长条件下培养韦氏乳杆菌，目的是刺激新的乳杆菌的产生。这些培养物将被化学提取，并用一种叫做液相色谱和质谱联用的非常灵敏的技术进行彻底的研究。任何SMs将被分离出来，然后进行抗菌和抗真菌活性筛选。SMs还将研究它们在切叶蚁生态系统中的生态作用。这项研究还将开发出第一个基因工具来操纵韦伯氏大肠杆菌的基因组。这将允许靶向合成新SMs所需的特定基因，真菌中的SMs通常排列在所谓的多基因生物合成基因簇中。基因操作还将致力于设计出能够大量生产有价值的短毛细胞的新菌株。该项目将朝着确定新的有效抗生素迈出一步，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物研究的重要性。研究结果还将有助于更好地了解切叶蚁生态系统，并为研究其他微生物群提供化学和遗传工具。

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.