Developing of a tool-kit of chemical probes for bioimaging of microbial virulence

越来越多的耐多药微生物的出现导致世界卫生组织呼吁采取行动对抗抗菌素耐药性（AMR）。为了控制传染病的传播，如当前的COVID-19大流行，并提高健康水平，开发具有新型作用机制的新型抗菌药物至关重要。对现有抗生素的疗效差和严重的抗微生物耐药性（AMR）上升是目前控制和根除传染病的主要挑战。结核分枝杆菌（Mtb）、烟曲霉或白色念珠菌等病原体利用分泌的毒力因子挑战正常的免疫反应，避免杀死宿主内的巨噬细胞，从而建立感染。然而，微生物存活的机制和宿主对感染的反应仍然知之甚少。本项目旨在利用荧光探针开发特异性和选择性的化学配体来靶向关键毒力因子，并利用生物成像技术进一步研究其在发病机制中的作用。从这些研究中获得的知识将促进我们对宿主-病原体相互作用的理解，并为未来对抗感染的新疗法提供基础。该项目为现实生活中关键发病过程的生物成像提供了一种令人兴奋的新方法，具有潜在的新疗法应用前景。该项目将涉及多学科方法，包括计算化学和结构生物学（Tabernero）、药物化学和有机合成（Butterworth），以及生化和成像技术。该项目的合作性质是一个独特的机会，可以参与跨学科的工作环境，并且管理团队的互补专业知识意味着学生将在博士学位期间获得更广泛和全面的培训。

The increasing emergence of multi-drug-resistant microorganisms has led the World Health Organisation to plead for action against antimicrobial resistance (AMR). In order to control the spread of infectious diseases, such as the current COVID-19 pandemic, and to improve standard of health, is critical that new classes of antimicrobial agents with novel mechanisms of action are developed. Poor efficacy and the rising of severe anti microbial resistance (AMR) to current antibiotics is now the main challenge to control and eradicate infectious diseases.Pathogens like Mycobacterium tuberculosis (Mtb), Aspergillus fumigatus or Candida Albicans, use secreted virulence factors to challenge the normal immune response and avoid killing within host macrophages, thus establishing infection. However, the mechanisms of microbial survival and the host response to infection are still poorly understood.This projects aims to develop specific and selective chemical ligands with fluorescent probes to target critical virulence factors to further study their role in pathogenesis using bio-imaging techniques. The knowledge gained from these investigations will advance our understanding of host-pathogen interactions and provide the basis for future new therapies to fight infections.This project offers an exciting new approach to bioimaging critical pathogenesis processes in real life with potential applications for novel therapies. The project will involve a multidisciplinary approach with computational chemistry and structural biology (Tabernero), medicinal chemistry and organic synthesis (Butterworth), together with biochemical and imaging technologies. The collaborative nature of the project is a unique opportunity to engage in an interdisciplinary working environment and the complementary expertise of the supervisory team means that the student will have a much broader and rounded up training during the PhD.