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：
9789825
负责人：
Christian Corey Melander
金额：
$ 73.52万
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/9789825
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 pneumonia bacterium 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 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给人类带来了巨大的持续挑战公共卫生。粘菌素是一种具有明显肾毒性的多粘菌素抗生素，现在被认为是最后的抗生素治疗这些感染的手段。随着粘菌素使用的重新流行，耐粘菌素的分离株也出现了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。为了对抗由于粘菌素耐药性的威胁日益严重，我们启动了一项研究计划来识别小分子，称为抗生素佐剂，调节粘菌素对抗 MDR 革兰氏阴性病原体的活性。我们有确定了可将粘菌素的最低抑制浓度 (MIC) 降低 2048 倍的分子对粘菌素敏感和对粘菌素耐药的细菌（鲍曼不动杆菌、铜绿假单胞菌、肺炎克雷伯菌和大肠杆菌）。机理研究表明我们的先导化合物结合鲍曼不动杆菌中的反应调节因子 PmrA，下调 pmrCAB 操纵子，并逆转脂质 A 修改。由于粘菌素毒性是剂量依赖性的，这些化合物有可能降低治疗剂量因此，治疗耐多药革兰氏阴性菌可以减轻毒性。对于粘菌素耐药的情况细菌，这种方法将有助于将 MIC 抑制在临床定义的耐药断点以下并再次使粘菌素疗法能够有效治疗感染，否则可能没有有效的治疗方法抗生素。