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: 10728393
• 负责人: Steven D. Townsend
• 金额: $ 8.31万
• 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/10728393
• 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; Penetration; 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.

项目摘要 多重耐药革兰氏阴性菌感染是一个持续的挑战 健康事实上，6种“ESKAPE”病原体中的4种-最近被强调为造成大多数 医院获得性感染-是革兰氏阴性病原体。虽然很明显，新的抗生素， 革兰氏阴性菌感染是迫切需要的，在这方面取得的进展微乎其微， 自从针对革兰氏阴性菌引入一类新药以来，已经过去了50多年。的 开发新的抗生素来治疗这些病原体是复杂的，因为革兰氏阴性菌 细菌有一层不可穿透的膜，赋予其对抗菌剂的内在抗性。广大 该项目的目的是研究对抗革兰氏阴性病原体的糖缀合物。我们取得了 两项重大发现表明，人乳低聚糖（HMO）可能在这方面具有变革性意义。 请注意。首先，HMO会引起细菌行为的重大变化，对细菌的生长和繁殖产生强烈影响。 形成生物膜，帮助细菌存活的结构。我们还观察到， 作为有效的佐剂，通过增加细胞内靶向抗生素的活性， 磁导率这两个发现构成了本申请中提出的项目的基础。在 项目1我们寻求表征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联合治疗抗A。鲍曼不动杆菌，一种重要的革兰氏- 阴性病原体在项目3中，我们研究了莫莱霉素的化学和生物化学 糖肽，一种对革兰氏阴性病原体具有抗菌活性的罕见糖肽。虽然不 来源于牛奶，我们计划利用我们在母乳科学方面的经验，研究 柔红霉素这项工作的一个重要成果是对生物多样性类型的机械理解。 可以进入革兰氏阴性菌的化合物。

项目成果

Total Synthesis of the Photorhabdus temperata ssp. Cinereal 3240 Zwitterionic Trisaccharide Repeating Unit.

• DOI: 10.1021/acs.orglett.1c02023
• 发表时间: 2021-08-06
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Nguyen JM;Townsend SD
• 通讯作者: Townsend SD

Total Synthesis of Ervaoffine J and K.

Ervaoffine J 和 K 的全合成。

• DOI: 10.1002/chem.202303985
• 发表时间: 2024
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Hughes,AlexanderJ;Townsend,StevenD
• 通讯作者: Townsend,StevenD

Synthesis of the Aeromonas veronii strain Bs8 disaccharide repeating unit.

• DOI: 10.1016/j.carres.2022.108530
• 发表时间: 2022-04
• 期刊: Carbohydrate research
• 影响因子: 3.1
• 作者: Nguyen JM;Evans CS;Wright NM;Townsend SD
• 通讯作者: Townsend SD

Prospecting Human Milk Oligosaccharides as a Defense Against Viral Infections.

• DOI: 10.1021/acsinfecdis.0c00807
• 发表时间: 2021-02-12
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Moore RE;Xu LL;Townsend SD
• 通讯作者: Townsend SD

Synthesis as an Expanding Resource in Human Milk Science.

• DOI: 10.1021/jacs.1c05599
• 发表时间: 2021-07
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Lianyan L Xu;Steven D. Townsend