understand how the lung environment affects colistin treatment efficacy and to develop new therapeutic strategies to improve patient outcomes

了解肺部环境如何影响粘菌素治疗效果并开发新的治疗策略以改善患者的治疗效果

• 批准号: 2767794
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2767794
• 关键词: understand; how; lung; environment; affects

Cystic fibrosis (CF) affects >10,000 people in the UK. Early mortality characterises the disease, largelydriven by chronic lung infection and inflammatory airway wall damage. By adulthood >60% patientsare chronically infected with the Gram-negative organism, Pseudomonas aeruginosa (Pa). Currenttherapy is limited, and once infection is chronic, the best that can be achieved is 'suppression' ofbacterial load, usually with inhaled antimicrobials. The Strategic Research Centre for Pa infectionwas established by Prof Jane C Davies, with a focus on improving understanding of pathogenicmechanisms and therapies. Its partnership with the Royal Brompton Hospital's CF clinic, one of thelargest in Europe, through senior clinical academics, underpins the strong translational focus of theprogramme. The narrow pipeline of new antibiotics under development means that work to improveefficacy of existing agents is urgently needed.Colistin is the polymyxin antibiotic used most commonly to control chronic P. aeruginosa infection inCF. Unfortunately, whilst colistin is usually effective in suppressing infection, it is almost never ableto clear P. aeruginosa from the lungs once chronic infection is established. Intravenous colistin isalso used as a 'last-resort' agent in severe disease, and thus, the emergence of resistance topolymyxin antibiotics is a growing concern. Efforts to improve colistin efficacy have been hamperedby a poor understanding of the antibiotic's mode of action and the lack of knowledge around theimpact that the host environment has on bacterial susceptibility. Recent work from the Edwards lab,based in the MRC Centre for Molecular Bacteriology and Infection, has revealed that colistin targetsLPS in both the outer and cytoplasmic membranes, leading to bacterial lysis and killing (Sabnis et al.,2019). We have also shown that colistin resistance due to the mobile colistin resistance (MCR) familyof LPS modifying enzymes (Liu et al., 2016) is due to modification of LPS at the cytoplasmicmembrane (Sabnis et al., 2019).We exploited this information to develop a combination therapeutic approach to enhance colistinactivity. We found that the experimental antibiotic murepavadin caused the accumulation of LPS inthe cytoplasmic membrane of P. aeruginosa, which sensitised the bacterium >1000-fold to colistin mediated killing. Given the geographical heterogeneity in airway deposition of inhaled agentsrelated to airway narrowing and mucus plugging, and the resulting variability in drug concentrations,successful approaches to enhance efficacy of lower drug concentrations could have direct clinicalimpact.The crucial next step in this work is to determine how the host environment influences LPSprocessing and transport, which we hypothesise will have significant effects on colistin susceptibilityand therefore treatment outcomes. For example, during this work, we found that LPS released bybacteria exposed to colistin can sequester the antibiotic, rendering it ineffective. We also found thatthe presence of human serum renders P. aeruginosa tolerant of colistin. These findings indicate thatcolistin efficacy is affected by the in vivo environment, but this requires further investigation.

囊性纤维化（CF）在英国影响> 10,000人。早期死亡率是该疾病的特征，该疾病受到慢性肺部感染和炎症气道壁损害的驱动。成年> 60％的患者长期感染了革兰氏阴性生物，铜绿假单胞菌（PA）。电流疗法是有限的，一旦感染慢性，可以实现的最好的是肉食负荷的“抑制”，通常是用吸入的抗菌药物。由Jane C Davies教授建立的PA感染战略研究中心，重点是提高对致病机制和疗法的了解。通过高级临床学者，它与欧洲皇家医院（Royal Brompton Hospital）的CF诊所的合作关系是Programmeme的强烈翻译重点。急需开发的新抗生素的狭窄管道意味着迫切需要提高现有药物的效率的工作。-固定蛋白是最常用的多粘蛋白抗生素，用于控制慢性铜绿假单胞菌感染INCF。不幸的是，虽然结肠癌通常可以有效抑制感染，但一旦建立了慢性感染，几乎永远不会从肺中清晰地铜绿假单胞菌。静脉注射肠菌丝ISALSO用作严重疾病中的“最后一度”药物，因此，耐药性托托抑素抗生素的出现越来越关注。通过对抗生素的作用方式以及宿主环境对细菌易感性影响的影响不足的理解不足，因此对提高结肠素疗效的努力受到了阻碍。位于MRC分子细菌学和感染中心的Edwards Lab的最新工作表明，外部和细胞质膜中的colistin靶标的SSLPS导致细菌裂解和杀伤（Sabnis等，2019）。我们还表明，由于移动菌蛋白耐药性（MCR）lps lps的抗性酶的抗性（Liu等，2016）是由于胞质质膜上LPS的修饰所致（Sabnis等，2019）。我们利用了此信息。开发一种结合治疗方法来增强施加性。我们发现，实验性抗生素murepavadin导致LPS在铜绿假单胞菌的细胞质膜中积聚，该细菌将细菌> 1000倍敏感至1000倍对菌群介导的杀伤。鉴于吸入试剂的气道沉积中的地理异质性与气道变窄和粘液堵塞，以及药物浓度的差异，成功的方法可以提高较低药物浓度的疗效。宿主环境会影响LPSPROCOSESSing和运输，我们假设这将对结肠蛋白易感性和治疗结果产生重大影响。例如，在这项工作中，我们发现暴露于colistin的LPS释放的薄菌可以隔离抗生素，使其无效。我们还发现，人血清的存在使铜绿蛋白的铜绿假单胞菌耐受。这些发现表明colistin疗效受体内环境的影响，但这需要进一步研究。