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：
10005112
负责人：
Christian Corey Melander
金额：
$ 73.06万
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/10005112
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 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.

多药耐药性（MDR）革兰氏阴性细菌感染对公共卫生。 colistin是一种具有肾脏毒性的多聚牙毒素抗生素，现在被认为是最后一次的抗生素治疗这些感染的度假胜地。随着结肠素使用的复兴，抗colistin的抗菌株是现在变得越来越普遍，尤其是随着质粒传播的MCR-1基因的传播。打击我们越来越多地抗菌菌毒素的威胁，我们启动了一项研究计划，以识别所谓的小分子抗生素佐剂，可调节结肠蛋白对MDR革兰氏阴性病原体的活性。我们有鉴定出降低colistin的最小抑制浓度（MIC）的分子，最高为2048倍 colistin敏感性和抗组织素抗性细菌（baumannii，pseudomonas铜绿菌），铜绿菌，肺炎的克雷伯氏菌和大肠杆菌）。机械研究表明，我们的铅化合物结合 A. baumannii中的响应调节器PMRA，下调PMRCAB操纵子，并逆转脂质A 修改。由于结肠蛋白毒性取决于剂量，因此这些化合物对降低剂量的潜力 MDR革兰氏阴性细菌的治疗可以减轻毒性。如果是抗colis菌蛋白的细菌，这种方法将有助于抑制临床定义的电阻断裂点以下的麦克风并再次使肠菌丝疗法有效地治疗感染，否则可能没有有效的感染抗生素。