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

囊性纤维化是高加索人群中最常见的常染色体隐性遗传病。Cf是一种多系统疾病，会引起一系列临床症状，然而，进行性肺部疾病是诊断为该疾病的个人的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，对被诊断为CF的患者来说是一个重大的风险。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列为迫切需要新的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。抗毒力疗法的发展可能为治疗肺炎肺炎提供一种临床有效的手段，同时也可以对抗AMR危机。然而，由于其复杂的多菌环境，很难在体外模型中复制CF肺的条件。这给筛选新型抗菌剂带来了挑战，因为在简单的实验室介质中获得的结果通常不能反映体内的药物活性。当筛选抗毒力药物时，这种挑战会加剧，因为衡量细菌密度或活性的标准微生物终点不能提供对宿主-病原体相互作用的了解。一系列体外测试的使用，包括人工痰模型和表型分析，以及体内斑马鱼模型的使用，可能是分析重要的PA毒力因素和随后开发有效的抗毒力疗法的关键。

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.