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.

首席研究员/项目总监（最后、第一、中间）：Townsend, Steven D. 家长补助金摘要/摘要： 事实上，多重耐药（MDR）革兰氏阴性细菌感染是对公众健康的持续挑战。 最近强调的 4 种 ESKAPE 病原体是大多数医院获得性感染的原因 是革兰氏阴性病原体，尽管很明显，用于革兰氏阴性感染的新型抗生素是革兰氏阴性病原体。 尽管迫切需要，但在这方面进展甚微，而且距 针对革兰氏阴性菌推出了新型药物 开发了新的抗生素。 由于革兰氏阴性细菌具有不可穿透的膜，因此治疗这些病原体变得复杂 该项目的主要目标是研究对抗菌药物产生内在耐药性的因素。 我们的两项重大发现表明，糖复合物可以对抗革兰氏阴性病原体。 母乳低聚糖（HMO）在这方面可能具有变革性，首先，HMO 会带来重大变化。 细菌的行为，对生长和生物膜的形成有强烈的影响，有助于细菌的结构 我们还观察到 HMO 作为有效的佐剂，增强了细菌的活性。 这两项发现奠定了通过增加细胞通透性来靶向细胞内的抗生素的基础。 在本申请中提出的项目中，我们试图描述 HMO 对 Gram- 的影响。 在项目 2 中，我们将探索 HMO 的联合疗法。 鲍曼不动杆菌，一种重要的革兰氏阴性病原体，在项目 3 中我们研究了其化学和生物化学。 莫来霉素糖肽，一种罕见的糖肽，具有抗革兰氏阴性菌的抗菌活性 虽然病原体并非源自牛奶，但我们计划利用我们在母乳科学方面的经验来研究病原体。 这项工作的一个重要成果是对莫勒霉素类型的机械理解。 可以进入革兰氏阴性细菌的化合物。 补充摘要： 氨基糖苷类抗生素 (AGAs) 是强效广谱抗生素，具有卓越的活性 AGA 对抗需氧革兰氏阴性病原体的作用受到显着副作用的限制，其中之一是耳毒性。 或 AGA 引起的永久性听力损失影响约 20% 的患者群体。 最后，也许出乎意料的是，肾功能的快速侵蚀也是一个关键的副作用。 进化在 AGA 的使用中存在问题。该提案的重点是新颖的合成和生物学评估。 针对革兰氏阴性 ESKAPE 病原体（多重耐药细菌家族）的氨基糖苷衍生物。 合成 AGA 将接受细菌和真核核糖体抑制作用的筛选，代表 分别是抗菌活性和毒性。论文的结果将用于指导设计测定和分析。 下一代 AGA 的合成 该研究的目标是提供一组经过验证的先进 AGA。 对野生型和多重耐药革兰氏阴性菌表现出广泛而有效的抗生素活性， 毒性大大降低，适合未来开发。