Bioorganic Approaches Toward Novel Antimicrobial Agents Against 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引起细菌行为的重大变化，对生长和微生物生长产生强烈影响。 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。

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.