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

• 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
• 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

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.

多重耐药（MDR）鲍曼不动杆菌感染对公众提出了巨大的挑战 健康由于多药耐药的频繁发生，目前对A.鲍曼不 感染有限。β-内酰胺类抗生素，特别是碳青霉烯类，代表了治疗 易感感染。然而，碳青霉烯耐药越来越普遍，对于此类感染， 在最佳替代疗法上没有达成共识。因为迄今为止， 尽管有害的副作用是常见的，但粘菌素已经成为一种受欢迎的治疗方法。 然而，A.鲍曼不动杆菌越来越常见， 质粒携带的粘菌素耐药基因（mcr-1-10）进入医疗机构。不幸的是，最近的轨道 对革兰氏阴性菌有活性的新抗生素的发现记录非常少， 再加上大型制药公司退出抗生素发现，使得新疗法的开发， 非传统的治疗方法至关重要。为了应对这一日益严重的威胁，我们启动了一项研究计划， 鉴定称为抗生素佐剂的小分子，其增强大环内酯类抗MDR A的活性。 鲍曼不动杆菌。为此，我们已经成功地鉴定了降低最低抑制浓度的分子。 克拉霉素对一组主要临床A的所有成员的MIC高达512倍。 从沃尔特里德陆军研究所（WRAIR）分离的鲍曼不动杆菌几乎包括所有 临床相关A.鲍曼氏分支。佐剂也增强万古霉素的活性高达256倍。两 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， 穿过革兰氏阴性菌的外膜，机制研究已经导致了一个工作假设， 这些化合物通过增加外膜的渗透性来克服这种屏障 脂寡糖（LOS）的产生。佐剂与克拉霉素的组合在Galleria中有效 已显示其可预测小鼠感染模型中的结果， MDR A的背景。鲍曼不动杆菌。因此，此类佐剂与克拉霉素或克拉霉素的组合物是有效的。 万古霉素可形成治疗MDR A的有效方法的基础。鲍曼不动杆菌感染， 没有有效的抗生素。