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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：
10468029
负责人：
Christian Corey Melander
金额：
$ 72.09万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468029
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 antibiotic class 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人类构成了巨大的持续挑战公共卫生粘菌素是一种多粘菌素类抗生素，具有明显的肾毒性，现在被认为是最后一种抗生素。治疗这些感染的方法。随着粘菌素使用的复苏，尤其是随着质粒携带的mcr-1基因的传播，现在变得更加普遍。打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，以确定小分子，称为抗生素佐剂，其调节粘菌素对抗MDR革兰氏阴性病原体的活性。我们有鉴定了将粘菌素的最低抑制浓度（MIC）降低高达2048倍的分子，粘菌素敏感性和粘菌素抗性细菌（鲍氏不动杆菌，铜绿假单胞菌，肺炎克雷伯氏菌和大肠杆菌）。机制研究表明我们的先导化合物 A.鲍曼不动杆菌，下调pmrCAB操纵子，逆转脂质A 改性由于粘杆菌素毒性是剂量依赖性的，因此这些化合物降低用于治疗的剂量的潜力是有限的。 MDR革兰氏阴性菌的治疗可由此减轻毒性。在粘菌素耐药的情况下，细菌，这种方法将有助于抑制MIC低于临床定义的耐药断点并再次使粘菌素治疗有效地治疗感染，否则可能对这些感染无效，抗生素

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Natural products as inspiration for the development of bacterial antibiofilm agents.

DOI：
10.1039/d0np00022a
发表时间：
2020-11-01
期刊：
Natural product reports
影响因子：
11.9
作者：
Melander RJ;Basak AK;Melander C
通讯作者：
Melander C

Overcoming intrinsic resistance in gram-negative bacteria using small molecule adjuvants.

使用小分子佐剂克服革兰氏阴性菌的内在耐药性。

DOI：
10.1016/j.bmcl.2022.129113
发表时间：
2023
期刊：
Bioorganic & medicinal chemistry letters
影响因子：
2.7
作者：
Melander,RobertaJ;Mattingly,AnneE;Nemeth,AnsleyM;Melander,Christian
通讯作者：
Melander,Christian

Sensitization of Gram-Negative Bacteria to Aminoglycosides with 2-Aminoimidazole Adjuvants.

DOI：
10.3390/antibiotics12111563
发表时间：
2023-10-25
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
0
作者：
通讯作者：

Simple Dipyrrin Analogues of Prodigiosin for Use as Colistin Adjuvants.

DOI：
10.1002/cmdc.202200286
发表时间：
2022-08-17
期刊：
CHEMMEDCHEM
影响因子：
3.4
作者：
Siwawannapong, Kittipan;Nemeth, Ansley M.;Melander, Roberta J.;Rong, Jie;Davis, Jonathan R.;Taniguchi, Masahiko;Carpenter, Morgan E.;Lindsey, Jonathan S.;Melander, Christian
通讯作者：
Melander, Christian

Eukaryotic phosphatase inhibitors enhance colistin efficacy in gram-negative bacteria.