权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10708102
负责人：
Christian Corey Melander
金额：
$ 73.96万
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/10708102
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 Multi-Drug Resistance Multidrug-resistant Acinetobacter Multiple Bacterial Drug Resistance O Antigens Outcome Permeability Pharmaceutical Preparations Plasma Plasma Proteins Predisposition 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.

多药耐药鲍曼不动杆菌感染是公众面临的一个巨大挑战