New Drugs for CF Bugs: testing anti-virulence therapies against Pseudomonas aeruginosa in Cystic Fibrosis

治疗囊性纤维化病菌的新药：测试针对囊性纤维化的铜绿假单胞菌的抗毒力疗法

• 批准号: 2749994
• 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-2749994
• 关键词: New; Drugs; CF; Bugs; testing

Cystic Fibrosis (CF) is the most prevalent autosomal recessive disease amongst the Caucasian population. CF is a multisystemic disorder, causing an array of clinical symptoms, however, progressive lung disease is the main cause of morbidity and mortality rates in individuals diagnosed with the disorder. Of the bacteria comprising these infections, Pseudomonas aeruginosa (Pa) most commonly presents to clinical practise, and thus, represents a significant risk to patients diagnosed with CF. Antibiotic resistance (AMR) symbolizes a major global health threat, with the WHO placing Pa as a priority pathogen that desperately requires new treatment strategies. CF patients are regularly treated with aggressive antibiotic therapy, particularly during periodic pulmonary exacerbations. The development of anti-virulence therapeutics may provide a clinically effective means of treating Pa lung infections whilst also combatting the AMR crisis. However, due to its complex polymicrobial environment, it is difficult to replicate the conditions of the CF lung within in vitro models. This poses challenges when screening novel antimicrobial agents, as results obtained in simple laboratory media do not often reflect drug activity in vivo. Such challenges are exacerbated when screening anti-virulence drugs, as standard microbiological endpoints that measure bacterial density or viability do not provide an understanding of host-pathogen interactions. The utilisation of an array of in vitro assays including artificial sputum models and phenotypic assays, and in vivo zebrafish models may be key in the analysis of significant Pa virulence factors and the subsequent development of effective anti-virulence therapies.

囊性纤维化（CF）是高加索人群中最常见的常染色体隐性遗传疾病。CF是一种多系统疾病，引起一系列临床症状，然而，进行性肺部疾病是诊断患有该疾病的个体中发病率和死亡率的主要原因。在构成这些感染的细菌中，铜绿假单胞菌（Pa）最常出现在临床实践中，因此对诊断为CF的患者构成显著风险。抗生素耐药性（AMR）象征着一个重大的全球健康威胁，世卫组织将Pa列为迫切需要新治疗策略的优先病原体。CF患者定期接受积极的抗生素治疗，特别是在周期性肺恶化期间。抗毒力治疗剂的开发可以提供治疗Pa肺部感染的临床有效手段，同时也对抗AMR危机。然而，由于其复杂的多微生物环境，很难在体外模型中复制CF肺的条件。这在筛选新型抗菌药物时带来了挑战，因为在简单实验室培养基中获得的结果通常不能反映体内药物活性。当筛选抗毒力药物时，这些挑战加剧，因为测量细菌密度或活力的标准微生物终点不能提供对宿主-病原体相互作用的理解。利用一系列体外测定，包括人工痰模型和表型测定，以及体内斑马鱼模型，可能是分析重要Pa毒力因子和随后开发有效抗毒力疗法的关键。