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: 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
• 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

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对公众构成巨大的持续挑战 健康。由于多药耐药的频繁发生，目前鲍曼不动杆菌的治疗方案 感染是有限的。B-内酰胺类抗生素，特别是碳青霉烯类，代表着治疗的选择 易受感染。然而，碳青霉烯类耐药越来越普遍，对于这种感染， 对于最佳替代治疗方案，目前还没有达成共识。因为到目前为止，抵抗力相对来说 不同寻常的是，粘菌素已经成为一种受欢迎的治疗方法，尽管有害的副作用很常见。 然而，鲍曼不动杆菌对粘菌素的耐药性正在变得更加频繁，因为最近 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，最近的曲目 发现对革兰氏阴性细菌有效的新抗生素的记录非常糟糕， 再加上大型制药公司退出抗生素发现，使得新疗法和 非传统治疗方法至关重要。为了对抗这种日益增长的威胁，我们发起了一项研究计划，以 识别被称为抗生素佐剂的小分子，它们增强大环内酯类化合物对MDR A的活性。 鲍曼尼。为此，我们已经成功地确定了降低最低抑制率的分子 克拉霉素对所有原发临床A组成员的最低抑菌浓度(MIC)高达512倍。 鲍曼氏杆菌分离自沃尔特里德陆军研究所(WRAIR)，该研究所几乎涵盖了 临床相关的鲍曼假丝核菌分支。佐剂还可以增强万古霉素的活性，最高可达256倍。两者都有 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，因为它们不能 穿过革兰氏阴性细菌的外膜，机制研究导致了一个工作假说 这些化合物通过抑制增加外膜的通透性来克服这一障碍。 脂低聚糖(LOS)生产。佐剂与克拉霉素的联合治疗在鸡冠状杆菌中有效 梅隆氏菌感染模型，已被证明可在小鼠感染模型中预测结果 鲍曼氏多药耐药菌的背景。因此，这种佐剂与克拉霉素或克拉霉素的组合 万古霉素可能成为治疗鲍曼不动杆菌多药耐药感染的有效方法的基础 目前还没有有效的抗生素。