Colistin resistance in extensively drug-resistant Gram-negative pathogens

广泛耐药革兰氏阴性病原体中的粘菌素耐药性

• 批准号: 10374062
• 负责人: Yohei Doi
• 金额: $ 46.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374062
• 关键词: Acinetobacter baumannii; Address; Adjuvant; Antibiotics; Bacteria; Bacterial Pneumonia; Basic Science; Biological Assay; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Chemicals; Clinical; Clinical Microbiology; Clinical Research; Colistin; Detection; Dose; Drug Kinetics; ESKAPE pathogens; Enterobacter; Failure; Funding; Galactosamine; Glycolipids; Gram-Negative Bacteria; Hospitals; Human; In Vitro; Infection; Interdisciplinary Study; Investigation; Klebsiella pneumoniae; Knowledge; Laboratories; Lipid A; Lipids; Lipopolysaccharides; Lung infections; Mediating; Membrane; Methods; Modeling; Modification; Morbidity - disease rate; Mus; Mutation; Outcome; Patients; Pneumonia; Polymyxins; Predisposition; Protocols documentation; Pseudomonas aeruginosa; Resistance; Series; Site; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure of parenchyma of lung; Synthesis Chemistry; System; Testing; Tube; acronyms; appropriate dose; bacterial resistance; base; clinically relevant; colistin resistance; experimental study; extensive drug resistance; improved; in vitro activity; in vivo; insight; liquid chromatography mass spectrometry; mortality; novel; pathogen; phosphoethanolamine; pressure; prospective; public health priorities; resistance mechanism; resistant strain; side effect; small molecule; ventilator-associated pneumonia

Extensive drug resistance (XDR) in Gram-negative bacteria is widely recognized as a top priority public health issue. Colistin is often the only viable treatment option for infections caused by such pathogens, but morbidity and mortality are substantial even with colistin treatment. Furthermore, clinical use of colistin has led to the emergence of colistin-resistant strains. We have shown, for Acinetobacter baumannii and Klebsiella pneumoniae, that colistin resistance arises during therapy primarily due to modifications of lipid A, the membrane anchor component of the Gram-negative lipopolysaccharide, with amino-containing moieties such as aminoarabinose and phosphoethanolamine, and alternatively galactosamine, primarily mediated through specific mutations in the PmrAB or PhoPQ two-component regulatory systems. We have also demonstrated that rapid profiling of lipid A can serve as a reliable method to predict colistin susceptibility and resistance, an important advance given challenges associated with conventional susceptibility testing of colistin. Meanwhile, pharmacokinetic-based dosing of colistin has been widely implemented in the hope of improving its efficacy but without tangible clinical benefits so far. Our previous investigations have deepened understanding of colistin resistance mechanisms and their implications in A. baumannii, but also identified new knowledge gaps. These include wide ranges of resistance observed in the presence of lipid A modifications with colistin MICs ranging from 4 mg/L to >256 mg/L, difficulties with defining colistin MICs in some strains, and apparent disconnect between in vitro activity and suboptimal clinical outcome, especially among patients with pneumonia. Importantly, in vitro MICs may not always reflect in vivo efficacy of colistin due to remodeling of lipid A that occurs in the host, with or without selective pressure from colistin, and this may account for clinical failure in patients who are treated with ostensibly appropriate doses of colistin. This project aims to address these issues by quantifying resistance-conferring amino-containing lipid A moieties in clinical strains with a wide range of MICs among XDR Gram-negative pathogens, elucidating lipid A remodeling of XDR Gram-negative bacteria in the BAL fluid and the lung tissue of mice with pneumonia, determining lipid A modification directly in BAL specimens of patients infected with XDR Gram-negative pathogens, and correlating the ability of colistin adjuvants to abrogate colistin resistance to levels of Lipid A modification. The proposal therefore advances our understanding of colistin resistance across various XDR pathogens, fills a critical knowledge gap that lies between in vitro and in vivo resistance to colistin, and explores novel colistin adjuvants in abrogating lipid A modifications and colistin resistance. This comprehensive effort will be realized by close and ongoing multidisciplinary collaboration representing clinical microbiology, glycolipidomics, and synthetic chemistry.

革兰氏阴性菌广泛耐药（XDR）被广泛认为是最优先的公共卫生问题。粘菌素通常是由这些病原体引起的感染的唯一可行的治疗选择，但即使使用粘菌素治疗，发病率和死亡率也很高。此外，粘菌素的临床使用导致了粘菌素耐药菌株的出现。我们已经证明，对于鲍曼不动杆菌和肺炎克雷伯菌，在治疗期间产生粘菌素耐药性主要是由于脂质A的修饰，脂质A是革兰氏阴性脂多糖的膜锚组分，具有含氨基的部分，如氨基阿拉伯糖和磷酸乙醇胺，或者半乳糖胺，主要通过PmrAB或PhoPQ双组分调节系统中的特异性突变介导。我们还证明了脂质A的快速分析可以作为预测粘菌素敏感性和耐药性的可靠方法，这是一个重要的进步，因为与粘菌素的传统敏感性测试相关的挑战。同时，基于药代动力学的多粘菌素给药已被广泛应用，以期提高其疗效，但迄今为止尚未获得切实的临床益处。我们的前期研究加深了对粘菌素耐药机制及其在A. baumannii，但也发现了新的知识差距。这些包括在存在脂质A修饰的情况下观察到的广泛耐药性，粘菌素MIC范围为4 mg/L至>256 mg/L，在某些菌株中难以定义粘菌素MIC，以及体外活性与次优临床结果之间的明显脱节，特别是在肺炎患者中。重要的是，体外MIC可能并不总是反映粘菌素的体内疗效，这是由于在宿主中发生的脂质A重塑，有或没有来自粘菌素的选择性压力，这可能是用表面上适当剂量的粘菌素治疗的患者临床失败的原因。该项目旨在通过定量XDR革兰氏阴性病原体中具有广泛MIC范围的临床菌株中赋予耐药性的含氨基脂质A部分，阐明肺炎小鼠的BAL液和肺组织中XDR革兰氏阴性细菌的脂质A重塑，直接测定感染XDR革兰氏阴性病原体的患者的BAL标本中的脂质A修饰，以及将粘菌素佐剂消除粘菌素抗性的能力与脂质A修饰的水平相关联。因此，该提案推进了我们对各种XDR病原体的粘菌素耐药性的理解，填补了体外和体内对粘菌素耐药性之间的关键知识空白，并探索了消除脂质A修饰和粘菌素耐药性的新型粘菌素佐剂。这一全面的努力将通过代表临床微生物学、糖脂组学和合成化学的密切和持续的多学科合作来实现。