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

铜绿假单胞菌是一种普遍存在的机会致病菌，被世界卫生组织列为优先致病菌之一，开发新的治疗方法对其治疗至关重要。PA对10-20%的医院感染负有责任，并具有一套治疗耐药机制。许多PA抗性机制是内在的；然而，PA很容易通过适应特性和获得新的遗传物质来获得和利用进一步的机制。抗菌素耐药PA是囊性纤维化(CF)患者(英国约10,000人，全球约100,000人)和非囊性纤维支气管扩张症患者(仅在英国就有50,000-300,000人)发病率和死亡率的主要原因。一旦PA菌株定植于CF肺，就会产生多药耐药感染，从而迅速减少治疗选择。这些耐多药感染变得无法根除，导致肺功能急剧丧失。此前，一个不同的商业大环化合物文库针对多药耐药PA的临床菌株进行了筛选。产生了新的热门药物；这些药物要么是增强现有抗生素的抗药性破坏剂，要么是直接作用的抗菌剂，抑制耐药PA。使用化学信息学方法对化合物进行分类和排序，然后建立重新合成和衍生优先化合物的化学合成路线。这项研究将包括使用微生物学、基因组和化学蛋白质组学方法相结合的方法来研究优先打击耐药PA的机制。优先命中将针对已知的耐药PA菌株进行分析，以证明与已知的抗生素或增强剂有任何交叉耐药性。全基因组测序将用于建立和识别已知耐药菌株相对于基线菌株的抗药性突变。对于化学蛋白质组学方法，将使用模拟所选HITS的结构和生物活性的光反应化学探针来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目标之间的相互作用。这一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。总体目标是促进抗菌素耐药性的研究和抗生素的发现。

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.