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Development of Antibiotic Adjuvants for Gram-Negative Bacteria

革兰氏阴性菌抗生素佐剂的开发

基本信息

批准号：
10224707
负责人：
Christian Corey Melander
金额：
$ 72.58万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-21 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224707
关键词：
Acinetobacter baumannii Acute Address Adjuvant Affect Antibiotic Resistance Antibiotics Area Back Bacteria Bacterial Infections Binding Biophysics Cells Chemicals Clinic Clinical Colistin Crystallization Daptomycin Development Dose Drug resistance Eligibility Determination Escherichia coli Future Genes Genetic Transcription Gram-Negative Bacteria Gram-Negative Bacterial Infections Gram-Positive Bacteria Infection Kidney Klebsiella pneumoniae Lead Libraries Linezolid Lipid A Lung Medical Minimum Inhibitory Concentration measurement Modification Morbidity - disease rate Multi-Drug Resistance Multiple Bacterial Drug Resistance NMR Spectroscopy Operon Organism Outcome Oxazolidinones Patients Pharmaceutical Preparations Phenotype Plasmids Polymyxins Predisposition Protocols documentation Pseudomonas aeruginosa Public Health Regimen Renal function Research Resistance Resort Roentgen Rays Structure Toxic effect Work analog antimicrobial drug bacterial resistance bactericide base blind colistin resistance combat design dosage efficacious treatment experimental study genetic selection in vivo mortality mouse model nephrotoxicity next generation novel novel strategies novel therapeutics pathogen pathogenic bacteria pharmacokinetics and pharmacodynamics programs resistance gene response scaffold screening small molecule therapeutic effectiveness transposon sequencing

项目摘要

Multi-drug resistant (MDR) Gram-negative bacterial infections present an enormous ongoing challenge to public health. Colistin, a polymyxin antibiotic with noted renal toxicity, is now considered an antibiotic of last resort for the treatment of these infections. With the resurgence in colistin use, colistin-resistant isolates are now becoming more common, especially with the spread of the plasmid-borne mcr-1 gene. To combat the growing threat of colistin-resistance, we initiated a research program to identify small molecules, termed antibiotic adjuvants, that modulate the activity of colistin against MDR Gram-negative pathogens. We have identified molecules that lower the minimum inhibitory concentration (MIC) of colistin up to 2048-fold against both colistin-sensitive and colistin-resistant bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli). Mechanistic studies have shown that our lead compound binds the response regulator PmrA in A. baumannii, downregulates the pmrCAB operon, and reverses lipid A modification. As colistin toxicity is dose dependent, the potential of these compounds to lower dosages for the treatment of MDR Gram-negative bacteria could thereby mitigate toxicity. In the case of colistin-resistant bacteria, this approach would serve to suppress the MIC below the clinically defined breakpoint for resistance and again render colistin therapy efficacious to treat infections for which otherwise there may be no effective antibiotics.

多重耐药(MDR)革兰氏阴性细菌感染对公共卫生。粘菌素是一种多粘菌素抗生素，具有明显的肾脏毒性，现在被认为是最后一种抗生素。求助于这些感染的治疗。随着粘菌素使用的卷土重来，对粘菌素具有抗药性的菌株现在变得越来越普遍，特别是随着质粒携带的mcr-1基因的传播。为了抗击由于粘菌素耐药性的威胁越来越大，我们启动了一项研究计划，以识别名为抗生素佐剂，调节粘菌素对抗多药耐药革兰氏阴性病原体的活性。我们有识别出可将粘菌素的最低抑菌浓度(MIC)降低2048倍的分子粘菌素敏感和耐粘菌素细菌(鲍曼不动杆菌，铜绿假单胞菌，肺炎克雷伯氏菌、大肠埃希菌)。机械学研究表明，我们的铅化合物结合在一起鲍曼不动杆菌中的反应调节因子PmrA下调pmrCAB操纵子，逆转A类脂蛋白修改。由于粘菌素的毒性是剂量依赖性的，这些化合物可能会降低因此，对耐多药革兰氏阴性菌的治疗可以减轻毒性。在对粘菌素耐药的情况下细菌，这种方法将有助于将MIC抑制在临床定义的耐药临界点以下并再次使粘菌素疗法有效地治疗原本可能无效的感染。抗生素。