Developing novel antimicrobial macrocycles against multidrug resistant bacteria that cause chronic lung infections

开发针对引起慢性肺部感染的多重耐药细菌的新型抗菌大环化合物

• 批准号: 2750362
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2750362
• 关键词: Developing; novel; antimicrobial; macrocycles; against

Pseudomonas aeruginosa (Pa) is a ubiquitous opportunistic pathogen, classified by WHO as a priority one pathogen, for which the development of new therapeutics is critical. Pa is responsible for 10-20% of nosocomial infections and possesses a suite of therapeutic resistance mechanisms. Many Pa resistance mechanisms are intrinsic; however, Pa readily acquires and utilises further mechanisms via adaptive traits, and the acquisition of new genetic material. Antimicrobial resistant Pa is a major cause of morbidity and mortality in cystic fibrosis (CF) patients (~10,000 in the UK and ~100,000 worldwide) and people with non-CF bronchiectasis (50,000-300,000 in the UK alone). Once they have colonised the CF lung, Pa isolates can establish a multidrug resistant infection, rapidly reducing treatment options. These multidrug resistant infections become impossible to eradicate, leading to dramatic loss of lung function. Previously, a divergent commercial macrocycle compound library was screened against clinical strains of multidrug resistant Pa. Novel hits were generated; these were either resistance-breakers which potentiated existing antibiotics, or direct-acting antimicrobials which inhibited resistant Pa. A cheminformatics approach was used to cluster and prioritise the compounds, and chemical synthetic routes for resynthesis and derivation of the prioritised compounds were then established. The research will encompass investigations of the mechanisms of the prioritised hits against resistant Pa using a combination of microbiological, genomic, and chemical proteomics approaches. The prioritised hits will be profiled against known resistant Pa strains to evidence any cross-resistance with known antibiotics or potentiators. Whole genome sequencing will be used to establish and identify mutations conferring resistance in known resistant isolates relative to baseline strains. For the chemical proteomics approach, photoreactive chemical probes mimicking structures and biological activities of the selected hits will be used to tag and enrich protein targets of interest. They will also be used to investigate the interactions between the chemical probes and potential targets at the molecular level. This interdisciplinary project intends to address a public health issue at the interfaces between medicinal chemistry, chemical biology, microbiology, and chem/bioinformatics. The overall aim is to further both antimicrobial resistance research and antibiotic discovery.

铜绿假单胞菌（Pa）是一种普遍存在的机会性病原体，被世卫组织列为重点病原体，为此开发新的治疗方法至关重要。Pa导致10-20%的医院感染，并具有一套治疗耐药机制。许多Pa阻力机制是内在的；然而，Pa很容易通过适应性状和获得新的遗传物质来获得和利用进一步的机制。抗微生物药物耐药性Pa是囊性纤维化（CF）患者（英国约10,000例，全球约100,000例）和非CF支气管扩张患者（仅在英国就有50,000-300,000例）发病率和死亡率的主要原因。一旦它们在CF肺中定植，Pa分离物可以建立多药耐药感染，迅速减少治疗选择。这些多重耐药感染变得无法根除，导致肺功能急剧丧失。此前，针对临床多药耐药Pa菌株筛选了不同的商业大环化合物文库。产生了新的热门作品；这些药物要么是增强现有抗生素的耐药抑制剂，要么是抑制耐药Pa的直接作用抗菌剂。使用化学信息学方法对化合物进行聚类和优先排序，然后建立优先化合物的再合成和衍生的化学合成路线。这项研究将包括利用微生物学、基因组学和化学蛋白质组学方法的结合，对耐药Pa的优先打击机制进行调查。将对已知耐药菌株进行优先打击，以证明与已知抗生素或增强剂的交叉耐药。全基因组测序将用于建立和鉴定相对于基线菌株的已知耐药分离株的耐药突变。对于化学蛋白质组学方法，光反应化学探针模拟所选hit的结构和生物活性，将用于标记和丰富感兴趣的蛋白质靶标。它们还将用于在分子水平上研究化学探针与潜在靶标之间的相互作用。该跨学科项目旨在解决药物化学、化学生物学、微生物学和化学/生物信息学之间的公共卫生问题。总体目标是进一步推进抗菌素耐药性研究和抗生素发现。