Barton Thomas E, Frost Frederick, Fothergill Joanne L, Neill Daniel R
Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Ronald Ross Building, 8 West Derby Street, Liverpool, L69 7BE, UK.
Adult Cystic Fibrosis Centre, Liverpool Heart & Chest Hospital NHS Foundation Trust, Liverpool, UK.
J Med Microbiol. 2022 Dec;71(12). doi: 10.1099/jmm.0.001643.
Chronic respiratory infection is the primary driver of mortality in individuals with cystic fibrosis (CF). Existing drug screening models utilised in preclinical antimicrobial development are unable to mimic the complex CF respiratory environment. Consequently, antimicrobials showing promising activity in preclinical models often fail to translate through to clinical efficacy in people with CF. Model systems used in CF anti-infective drug discovery and development range from antimicrobial susceptibility testing in nutrient broth, through to 2D and 3D tissue culture systems and models. No single model fully recapitulates every key aspect of the CF lung. To improve the outcomes of people with CF (PwCF) it is necessary to develop a set of preclinical models that collectively recapitulate the CF respiratory environment to a high degree of accuracy. Models must be validated for their ability to mimic aspects of the CF lung and associated lung infection, through evaluation of biomarkers that can also be assessed following treatment in the clinic. This will give preclinical models greater predictive power for identification of antimicrobials with clinical efficacy. The landscape of CF is changing, with the advent of modulator therapies that correct the function of the CFTR protein, while antivirulence drugs and phage therapy are emerging alternative treatments to chronic infection. This review discusses the challenges faced in current antimicrobial development pipelines, including the advantages and disadvantages of current preclinical models and the impact of emerging treatments.
慢性呼吸道感染是囊性纤维化（CF）患者死亡的主要驱动因素。临床前抗菌药物研发中使用的现有药物筛选模型无法模拟复杂的CF呼吸道环境。因此，在临床前模型中显示出有前景活性的抗菌药物在CF患者中往往无法转化为临床疗效。CF抗感染药物发现和开发中使用的模型系统范围从营养肉汤中的抗菌药物敏感性测试，到二维和三维组织培养系统及模型。没有单一模型能完全概括CF肺部的每个关键方面。为改善CF患者（PwCF）的治疗效果，有必要开发一组临床前模型，这些模型能高度准确地共同概括CF呼吸道环境。必须通过评估生物标志物来验证模型模拟CF肺部及相关肺部感染方面的能力，这些生物标志物在临床治疗后也可进行评估。这将赋予临床前模型更大的预测能力，以识别具有临床疗效的抗菌药物。随着纠正CFTR蛋白功能的调节剂疗法的出现，CF的格局正在发生变化，而抗毒力药物和噬菌体疗法正在成为慢性感染的替代治疗方法。本综述讨论了当前抗菌药物研发流程中面临的挑战，包括当前临床前模型的优缺点以及新兴治疗方法的影响。
