Repurposing Gram-positive Antibiotics for Gram-Negative Bacteria using Antibiotic Adjuvants

使用抗生素佐剂重新利用革兰氏阳性抗生素治疗革兰氏阴性菌

基本信息

批准号：
10587015
负责人：
Christian Corey Melander
金额：
$ 76.96万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587015
关键词：
Acinetobacter baumannii Acute Address Adjuvant Adjuvant Study Anabolism Animals Antibiotic Resistance Antibiotics Area Bacteria Bacterial Infections Baltimore Binding Proteins Biogenesis Biological Assay Carbapenems Clarithromycin Clinical Colistin Consensus Coupled Data Development Dose Drug Interactions Drug Kinetics Evaluation Goals Gram-Negative Bacteria Health care facility In Vitro Infection Intensive Care Units Lead Life Lipid A Lung Macrolides Maryland Measures Medical Membrane Membrane Proteins Metabolic Metabolism Minimum Inhibitory Concentration measurement Modeling Molecular Target Monobactams Multi-Drug Resistance Multidrug-resistant Acinetobacter Multiple Bacterial Drug Resistance O Antigens Outcome Permeability Pharmaceutical Preparations Plasma Plasma Proteins Plasmids Production Proteins Protocols documentation Public Health Reporting Research Research Institute Resistance Scourge Structure Structure-Activity Relationship Testing Therapeutic Tissues Toxic effect Universities Vancomycin Virulence Work alternative treatment analog antibiotic resistant infections antimicrobial drug beta-Lactams carbapenem resistance clinically relevant colistin resistance combat design in vitro activity in vivo lead optimization lipooligosaccharide member mortality mouse model novel strategies novel therapeutics optimal treatments outcome prediction pathogen pathogenic bacteria programs resistance frequency resistance gene resistance mechanism side effect small molecule treatment choice

项目摘要

Multi-drug resistant (MDR) Acinetobacter baumannii infections present an enormous ongoing challenge to public health. Due to the frequent occurrence of multidrug resistance, current treatment options for A. baumannii infections are limited. ß-Lactam antibiotics, especially carbapenems, represent the treatment of choice for susceptible infections. However, carbapenem resistance is increasingly common, and for such infections there is no consensus on the optimal alternative treatment. Because resistance has hitherto been relatively uncommon, colistin has become a favored treatment in spite of the fact that deleterious side effects are common. However, resistance to colistin in A. baumannii is becoming more frequent with the recent dissemination of plasmid-borne colistin resistance genes (mcr-1-10) into healthcare facilities. Unfortunately, the recent track record of discovery of new antibiotics that are active against Gram-negative bacteria is exceedingly poor, which, coupled with the exit of Big Pharma from antibiotic discovery, has made the development of new therapies and non-traditional therapeutic approaches vital. To combat this growing threat, we initiated a research program to identify small molecules, termed antibiotic adjuvants, that potentiate the activity of macrolides against MDR A. baumannii. To this end, we have successfully identified molecules that lower the minimum inhibitory concentration (MIC) of clarithromycin up to 512-fold against all members of a panel of primary clinical A. baumannii isolates from the Walter Reed Army Institute of Research (WRAIR) that encompasses nearly all clinically relevant A. baumannii clades. Adjuvants also potentiate the activity of vancomycin up to 256-fold. Both macrolides and vancomycin are typically viewed as “Gram-positive” selective antibiotics due to their inability to cross the outer membrane of Gram-negative bacteria, Mechanistic studies have led to a working hypothesis that these compounds overcome this barrier by increasing permeability of the outer membrane through inhibiting lipooligosaccharide (LOS) production. Combinations of adjuvant with clarithromycin are effective in a Galleria mellonella model of infection, which has been shown to predict outcome in murine models of infection in the context of MDR A. baumannii. Therefore, combinations of such adjuvants with either clarithromycin or vancomycin may form the basis for an efficacious approach to treating MDR A. baumannii infections for which there are no effective antibiotics.

多药耐药（MDR）鲍曼尼杆菌感染对公众带来了巨大的持续挑战健康。由于多药耐药性的频繁出现，鲍曼尼曲霉的当前治疗选择感染有限。 β-内酰胺抗生素，尤其是碳青霉烯代表选择的治疗方法易感感染。但是，碳青霉苯甲酸越来越普遍，对于此类感染对最佳替代治疗没有共识。因为阻力已隐藏相对尽管有害副作用很常见，但不常见的colistin已成为一种受欢迎的治疗方法。但是，随着最近的传播质粒传播的结肠蛋白耐药基因（MCR-1-10）进入医疗机构。不幸的是，最近的曲目针对革兰氏阴性细菌活跃的新抗生素发现发现的记录非常差，这是再加上抗生素发现的大药物出口，使新疗法的发展和非传统治疗方法至关重要。为了应对这一日益增长的威胁，我们启动了一项研究计划鉴定小分子，称为抗生素调节剂，可能会对大花环对MDR A的活性。鲍曼尼。为此，我们成功鉴定了降低最小抑制的分子克拉霉素的浓度（MIC）对一组原代临床A的所有成员最高512倍。来自沃尔特·里德陆军研究所（Wrair）的鲍曼尼氏菌分离，几乎全部临床上相关的鲍曼尼抗体。调节器还潜在可达256倍的万古霉素的活性。两个都大环内酯类和万古霉素通常被视为“革兰氏阳性”选择性抗生素，因为它们无法跨越革兰氏阴性细菌的外膜，机械研究导致了一个有效的假设，即这些化合物通过抑制外膜的渗透性来克服这一障碍 Lipoligosacachide（LOS）生产。与克拉霉素调整的组合在美术中有效感染的梅洛尼菌模型，已证明可以预测在鼠类感染模型中的结果 MDR A. Baumannii的背景。因此，这种调节器与克拉霉素或万古霉素可能是治疗MDR A. baumannii感染的有效方法的基础没有有效的抗生素。