Bioorganic Approaches Toward Novel Antimicrobial Agents Against Gram-Negative Bacteria

针对革兰氏阴性菌的新型抗菌剂的生物有机方法

• 批准号: 10620040
• 负责人: Steven D. Townsend
• 金额: $ 6.92万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620040
• 关键词: Acinetobacter baumannii; Adjuvant; Aerobic; Affect; Aminoglycoside Antibiotics; Aminoglycosides; Anti-Bacterial Agents; Antibiotics; Antimicrobial Resistance; Architecture; Bacteria; Behavior; Biochemistry; Biological; Biological Assay; Cells; Chemistry; Combined Modality Therapy; Development; ESKAPE pathogens; Evaluation; Evolution; Family; Foundations; Future; Glycoconjugates; Glycopeptides; Glycosides; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Growth; Human Milk; Infection; Membrane; Methods; Microbial Biofilms; Milk; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Nosocomial Infections; Oligosaccharides; Output; Permeability; Public Health; Renal function; Research Personnel; Resistance; Ribosomes; Science; Structure; Toxic effect; Work; antimicrobial; antimicrobial drug; combat; cytotoxicity; design; experience; human pathogen; insight; member; microbiome; nephrotoxicity; next generation; novel; novel drug class; ototoxicity; parent grant; pathogen; patient population; permanent hearing loss; programs; screening; side effect

Principle Investigator/Program Director (Last, first, middle): Townsend, Steven D. Parent Grant Summary/Abstract: Multi-drug resistant (MDR) Gram-negative bacterial infections are an ongoing challenge to public health. Indeed, 4 of the ESKAPE pathogens recently highlighted as responsible for the majority of hospital acquired infections are Gram-negative pathogens. Although it is clear that novel antibiotics for Gram-negative infections are desperately needed, there has been minimal progress in this regard, and it has been over five decades since a new class of drugs have been introduced for Gram-negative bacteria. The development of new antibiotics to treat these pathogens is complicated by the fact that Gram-negative bacteria have an impenetrable membrane that confers intrinsic resistance to antimicrobial agents. The broad objective of this program is to study glycoconjugates to combat Gram-negative pathogens. We have made two major discoveries that suggests human milk oligosaccharides (HMOs) may be transformative in this regard. First, HMOs cause major changes to the behavior of bacteria, with strong effects on growth and the formation of biofilms, architectures that aid in bacterial survival. We have also observed that HMOs function as potent adjuvants, potentiating the activity of intracellular-targeting antibiotics by increasing cell permeability. These two discoveries form the foundation of the projects proposed in this application. In Project 1 we seek to characterize the impact of HMOs on Gram- negative causes of microbiome imbalance. In Project 2 we will explore HMOs in combination therapies against A. baumannii, an important Gram- negative pathogen. In Project 3 we investigate the chemistry and biochemistry of the mollemycin glycopeptides, a rare glycopeptide with antimicrobial activity against Gram-negative pathogens. While not sourced from milk, we plan to leverage our experience in human milk science to study the biochemistry of the mollemycins. A significant output of this work is a mechanistic understanding of the types of compounds that can enter Gram-negative bacteria. Supplement Abstract: The aminoglycoside antibiotics (AGAs) are potent broad-spectrum antibiotics that show excellence activity against aerobic, gram-negative pathogens. AGAs are limited by significant side effects, one of which is ototoxicity or AGA‐induced permanent hearing loss. Ototoxicity affects ca. 20% of the patient population. Nephrotoxicity, or the rapid erosion of kidney function is also a key side effect. Lastly, and perhaps unexpectedly, resistance evolution is problematic in AGA usage. This proposal focuses on the synthesis and biological evaluation of novel aminoglycoside derivatives against gram-negative ESKAPE pathogens, a family of multidrug resistant bacteria. Synthetic AGAs will undergo screening for inhibition of bacterial and eukaryotic ribosomes, representative of antibacterial activity and toxicity, respectively. The results of these assays will be used to inform the design and synthesis of next generation AGAs. The goal of the study is to deliver a set of validated advanced AGAs that display broad and potent antibiotic activity against wild type and multidrug resistant gram-negative bacteria, with much reduced toxicity, suitable for future development.

主要调查员/计划总监（最后，第一，中间）：汤森，史蒂文·D。 父母赠款摘要/摘要： 多药耐药（MDR）革兰氏阴性细菌感染是对公共卫生的持续挑战。的确， 最近的4个病原体最近强调了大多数医院感染的原因 是革兰氏阴性病原体。尽管很明显，革兰氏阴性感染的新型抗生素是 迫切需要，在这方面取得了很小的进步，自一个多十年以来 已经引入了用于革兰氏阴性细菌的新药物。开发新的抗生素 治疗这些病原体使革兰氏阴性细菌具有不可穿透的膜，这使这些病原体变得复杂 这承认对抗菌剂的内在抗性。该计划的广泛目标是研究 糖缀合物以对抗革兰氏阴性病原体。我们已经提出了两个主要发现 在这方面，人乳寡糖（HMO）可能是变化的。首先，HMO会导致重大变化 对细菌的行为，对生长和生物膜的形成有强大影响 细菌生存。我们还观察到HMOS充当潜在的调节器，从而使 细胞内靶向抗生素通过增加细胞渗透性。这两个发现构成了 本应用程序中提出的项目。在项目1中，我们试图表征HMO对革兰氏集的影响 微生物组失衡的负面原因。在项目2中，我们将探索针对组合疗法的HMO A. Baumannii，一种重要的革兰氏阴性病原体。在项目3中，我们研究化学和生物化学 Mollemycin糖肽是一种罕见的糖肽，具有抗菌活性抗革兰氏阴性 病原体。虽然不是从牛奶中得出的，但我们计划利用我们在人类乳科学领域 Mollemycins的生物化学。这项工作的重要输出是对机械的理解 可以进入革兰氏阴性细菌的化合物。 补充摘要： 氨基糖苷抗生素（AGA）是潜在的广谱抗生素，显示出卓越活性 针对有氧，革兰氏阴性病原体。 AGA受到重大副作用的限制，其中之一是耳毒性 或AGA引起的永久性听力损失。耳毒性会影响Ca。 20％的患者人数。肾毒性，或 肾功能的快速侵蚀也是关键的副作用。最后，也许出乎意料的是抵抗 进化在AGA使用中是有问题的。该提议着重于新颖的合成和生物学评估 针对革兰氏阴性Eskape病原体的氨基糖苷衍生物，该病原体是多药耐药细菌的家族。 合成AGA将对细菌和真核核糖体的抑制进行筛查，代表 抗菌活性和毒性。这些测定结果将用于告知设计和 下一代Agas的合成。该研究的目的是提供一套经过验证的高级AGA 对野生型和耐多药抗革兰氏阴性细菌表现出广泛而潜在的抗生素活性，并具有 毒性大大降低，适合将来开发。