Anti-infective discovery from competitive ecosystems

点击翻译按钮获取中文摘要

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.