Protease activity sensors noninvasively classify bacterial infections and antibiotic responses.
Protease activity sensors noninvasively classify bacterial infections and antibiotic responses.
复制标题
DOI：
10.1016/j.ebiom.2018.11.031
复制
发表时间：
2018-12
期刊：
影响因子：
11.1
通讯作者：
Bhatia SN
中科院分区：
文献类型：
--
作者：
Buss CG;Dudani JS;Akana RTK;Fleming HE;Bhatia SN
呼吸道感染是一项重大的公共卫生风险，及时和准确地发现细菌感染有助于快速的治疗干预。此外，监测干预后感染的进展可以在最初治疗无效的情况下进行“路线纠正”，避免可能导致抗生素耐药性的不必要的药物剂量。然而，目前的诊断和监测技术依赖于非特异性或缓慢的读数，例如放射成像和痰培养，它们不能特异性地识别细菌感染，并且需要数天才能确定最佳的抗生素治疗。在这里，我们描述了一种纳米颗粒系统，该系统通过感知宿主和细菌蛋白酶活性来检测铜绿假单胞菌肺部感染，并提供尿液检测读数。一种蛋白酶传感器由铜绿假单胞菌蛋白酶LasA的肽底物组成。第二种用于检测弹性酶的传感器对重组中性粒细胞弹性酶和细菌菌株分泌的蛋白酶有反应。在感染铜绿假单胞菌的小鼠中，这些蛋白酶传感器的纳米颗粒配方——称为基于活性的纳米传感器（ABNs）——检测感染并监测肺部细菌清除。此外，abn在治疗开始后数小时内，能迅速区分适当和无效的抗生素治疗。这些发现表明，疾病相关蛋白酶的活性测量可以为细菌感染和解决的动态过程提供一个无创窗口，为检测、监测和表征肺部感染提供了机会。美国国家癌症研究所、美国国家环境健康科学研究所、美国国家卫生研究院、美国国家科学基金会研究生研究奖学金计划和霍华德休斯医学研究所。
Respiratory tract infections represent a significant public health risk, and timely and accurate detection of bacterial infections facilitates rapid therapeutic intervention. Furthermore, monitoring the progression of infections after intervention enables ‘course correction’ in cases where initial treatments are ineffective, avoiding unnecessary drug dosing that can contribute to antibiotic resistance. However, current diagnostic and monitoring techniques rely on non-specific or slow readouts, such as radiographic imaging and sputum cultures, which fail to specifically identify bacterial infections and take several days to identify optimal antibiotic treatments. Here we describe a nanoparticle system that detects P. aeruginosa lung infections by sensing host and bacterial protease activity in vivo, and that delivers a urinary detection readout. One protease sensor is comprised of a peptide substrate for the P. aeruginosa protease LasA. A second sensor designed to detect elastases is responsive to recombinant neutrophil elastase and secreted proteases from bacterial strains. In mice infected with P. aeruginosa, nanoparticle formulations of these protease sensors—termed activity-based nanosensors (ABNs)—detect infections and monitor bacterial clearance from the lungs over time. Additionally, ABNs differentiate between appropriate and ineffective antibiotic treatments acutely, within hours after the initiation of therapy. These findings demonstrate how activity measurements of disease-associated proteases can provide a noninvasive window into the dynamic process of bacterial infection and resolution, offering an opportunity for detecting, monitoring, and characterizing lung infections. National Cancer Institute, National Institute of Environmental Health Sciences, National Institutes of Health, National Science Foundation Graduate Research Fellowship Program, and Howard Hughes Medical Institute.
登录
查看更多内容
DOI：
10.1146/annurev-pathol-020712-164023
发表时间：
2014
期刊：
Annual review of pathology
影响因子：
--
作者：
Mayadas TN;Cullere X;Lowell CA
通讯作者：
Lowell CA
DOI：
10.1186/cc6105
发表时间：
2007
期刊：
Critical care (London, England)
影响因子：
--
作者：
Coelho L;Póvoa P;Almeida E;Fernandes A;Mealha R;Moreira P;Sabino H
通讯作者：
Sabino H
影响因子：
9.6
作者：
Iregui, M;Ward, S;Kollef, MH
通讯作者：
Kollef, MH
DOI：
10.1073/pnas.1805337115
发表时间：
2018-09-04
影响因子：
11.1
作者：
Dudani, Jaideep S.;Ibrahim, Maria;Bhatia, Sangeeta N.
通讯作者：
Bhatia, Sangeeta N.
DOI：
10.1093/cid/cit578
发表时间：
2013-12
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Caliendo AM;Gilbert DN;Ginocchio CC;Hanson KE;May L;Quinn TC;Tenover FC;Alland D;Blaschke AJ;Bonomo RA;Carroll KC;Ferraro MJ;Hirschhorn LR;Joseph WP;Karchmer T;MacIntyre AT;Reller LB;Jackson AF;Infectious Diseases Society of America (IDSA)
通讯作者：
Infectious Diseases Society of America (IDSA)