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.

多重耐药 (MDR) 鲍曼不动杆菌感染给公众带来了巨大的持续挑战 健康。由于多重耐药的频繁发生，鲍曼不动杆菌目前的治疗选择 感染是有限的。 β-内酰胺类抗生素，尤其是碳青霉烯类抗生素，代表了以下疾病的治疗选择： 易感染。然而，碳青霉烯类耐药性越来越普遍，对于此类感染 对于最佳替代治疗尚未达成共识。因为迄今为止阻力相对较小 尽管有害的副作用很常见，但粘菌素已成为一种受欢迎的治疗方法，但这种情况并不常见。 然而，随着最近鲍曼不动杆菌的传播，对粘菌素的耐药性变得越来越频繁。 质粒携带的粘菌素抗性基因 (mcr-1-10) 进入医疗机构。不幸的是，最近的曲目 对革兰氏阴性菌有活性的新抗生素的发现记录非常少，其中， 再加上大型制药公司退出抗生素研发领域，使得新疗法的开发和 非传统治疗方法至关重要。为了应对这一日益严重的威胁，我们启动了一项研究计划 鉴定出小分子，称为抗生素佐剂，可增强大环内酯类药物对抗 MDR A 的活性。 鲍曼氏菌。为此，我们已成功鉴定出降低最低抑制的分子 克拉霉素对初级临床 A 小组的所有成员的浓度 (MIC) 高达 512 倍。 鲍曼不动杆菌从沃尔特·里德陆军研究所 (WRAIR) 分离出来，该研究所几乎涵盖了所有 临床相关的鲍曼不动杆菌分支。佐剂还可将万古霉素的活性增强高达 256 倍。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 穿过革兰氏阴性细菌的外膜，机制研究得出了一个可行的假设： 这些化合物通过抑制增加外膜的渗透性来克服这一屏障 脂寡糖（LOS）的产生。佐剂与克拉霉素的组合在 Galleria 中有效 大蜡螟感染模型，已被证明可以预测小鼠感染模型的结果 MDR 鲍曼不动杆菌的背景。因此，此类佐剂与克拉霉素或 万古霉素可能为治疗多重耐药鲍曼不动杆菌感染的有效方法奠定基础。 没有有效的抗生素。