Bioorganic Approaches Toward Novel Antimicrobial Agents Against Gram-Negative Bacteria

项目摘要 多药耐药(MDR)革兰氏阴性细菌感染是公众面临的持续挑战 健康。事实上，6种“ESKAPE”病原体中的4种--最近被强调为导致大多数 医院获得性感染是革兰氏阴性病原体。尽管很明显，用于治疗的新型抗生素 革兰氏阴性菌感染是迫切需要的，在这方面取得的进展很小，而且已经 自从一类新的药物被引入治疗革兰氏阴性菌以来，已经有50多年了。这个 治疗这些病原体的新抗生素的开发因革兰氏阴性菌的事实而变得复杂 细菌有一层不透膜，对抗菌剂具有内在的抵抗力。《博大》 该计划的目的是研究糖结合物来对抗革兰氏阴性病原体。我们已经做出了 两项重大发现表明，人类乳寡糖(HMOS)可能在这方面具有变革性 敬重。首先，HMO引起细菌行为的重大变化，对细菌的生长和 生物膜的形成，有助于细菌生存的结构。我们还观察到，医疗保健组织 作为强大的佐剂，通过增加细胞数量来增强细胞内靶向抗生素的活性 渗透性。这两个发现构成了本申请中提出的项目的基础。在……里面 项目1我们试图描述HMOS对微生物群失衡的革兰氏阴性原因的影响。 在项目2中，我们将探索HMO在联合疗法中对抗鲍曼不动杆菌，一种重要的革兰氏菌- 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，一种罕见的对革兰氏阴性菌具有抗菌活性的糖肽。虽然不是 来源于牛奶，我们计划利用我们在母乳科学方面的经验来研究 软霉素。这项工作的一个重要成果是机械性地理解了 可以进入革兰氏阴性细菌的化合物。

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.