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: 10430181
• 负责人: Steven D. Townsend
• 金额: $ 29.95万
• 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/10430181
• 关键词: Acinetobacter baumannii; Adjuvant; Antibiotics; Antimicrobial Resistance; Architecture; Area; Bacteria; Behavior; Biochemistry; Cells; Chemistry; Combined Modality Therapy; Development; Drug resistance; ESKAPE pathogens; Foundations; Glycoconjugates; Glycopeptides; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Growth; Human Milk; Infection; Medical; Membrane; Microbial Biofilms; Microbiology; Milk; Multi-Drug Resistance; Nosocomial Infections; Oligosaccharides; Organism; Output; Permeability; Public Health; Resistance; Science; Work; antimicrobial; antimicrobial drug; chemical synthesis; combat; drug candidate; experience; microbiome; novel; novel drug class; novel strategies; pathogen; pathogenic microbe; programs

Project Summary Multi-drug resistant (MDR) Gram-negative bacterial infections are an ongoing challenge to public health. Indeed, 4 of the 6 “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.

项目概要 多重耐药 (MDR) 革兰氏阴性细菌感染是公众面临的持续挑战 事实上，6 种“ESKAPE”病原体中的 4 种最近被强调为造成大多数疾病的原因。 医院获得性感染是革兰氏阴性病原体，尽管新型抗生素可用于治疗。 革兰氏阴性菌感染是迫切需要的，但在这方面进展甚微，而且已经 自从针对革兰氏阴性菌推出一类新药物以来，已有五十多年了。 由于革兰氏阴性菌 细菌有一层不可穿透的膜，赋予其对抗菌药物的内在抵抗力。 该计划的目的是研究我们制造的糖复合物来对抗革兰氏阴性病原体。 两项重大发现表明母乳低聚糖 (HMO) 可能会在这方面带来变革 首先，HMO 会导致细菌行为发生重大变化，对生长和生长产生强烈影响。 我们还观察到 HMO 有助于形成生物膜，即有助于细菌生存的结构。 作为有效的佐剂，通过增加细胞活性来增强细胞内靶向抗生素的活性 这两项发现构成了本申请中提出的项目的基础。 项目 1 我们试图描述 HMO 对微生物组失衡的革兰氏阴性原因的影响。 在项目 2 中，我们将探索 HMO 在对抗鲍曼不动杆菌（一种重要的革兰氏杆菌）的联合疗法中的应用。 在项目 3 中，我们研究了莫来霉素的化学和生物化学。 糖肽，一种罕见的糖肽，对革兰氏阴性病原体具有抗菌活性。 源自牛奶，我们计划利用我们在母乳科学方面的经验来研究母乳的生物化学 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。