Bioorganic Approaches Toward Novel Antimicrobial Agents Against Gram-Negative Bacteria

主要研究者/项目负责人（最后，第一，中间）：汤森，史蒂文D。 家长补助金摘要/摘要： 多重耐药革兰氏阴性菌感染是公共卫生面临的一个持续挑战。的确， 最近强调的ESKAPE病原体中有4种是大多数医院获得性感染的原因 是革兰氏阴性病原体虽然很明显，用于革兰氏阴性菌感染的新型抗生素是 尽管迫切需要，但在这方面取得的进展微乎其微，而且自2000年以来已经过去了50多年。 针对革兰氏阴性菌已经引入了新的药物类别。新抗生素的开发， 革兰氏阴性菌有一层无法穿透的膜， 它赋予了对抗菌剂的内在抗性。该计划的主要目标是研究 糖缀合物来对抗革兰氏阴性病原体。我们有两项重大发现表明 人乳低聚糖（HMO）在这方面可能具有变革性。首先，健康维护组织引起重大变化， 细菌的行为，对生长和生物膜的形成有很大的影响， 细菌存活我们还观察到HMO作为有效的佐剂发挥作用， 细胞内靶向抗生素通过增加细胞渗透性。这两项发现构成了 本申请中提出的项目。在项目1中，我们试图描述HMO对革兰氏阴性菌的影响， 微生物失衡的原因。在项目2中，我们将探索HMO在联合治疗中的作用， A.鲍曼不动杆菌是一种重要的革兰氏阴性病原体。在项目3中，我们研究了化学和生物化学 一种对革兰氏阴性菌具有抗菌活性的罕见糖肽， 病原体虽然不是从牛奶中提取，但我们计划利用我们在母乳科学方面的经验来研究 柔红霉素的生物化学。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。 补充摘要： 氨基糖苷类抗生素（aminoglycosides antibiotics，AGA）是一种广谱、高效的抗生素 对抗需氧革兰氏阴性病原体AGA受到显著副作用的限制，其中之一是耳毒性 或阿加诱发的永久性听力损失。耳毒性影响CA。20%的患者。肾毒性，或 肾功能的迅速恶化也是一个重要的副作用。最后，也许出乎意料的是， 进化在阿加使用中是有问题的。本研究的重点是新的化合物的合成和生物学评价。 针对革兰氏阴性ESKAPE病原体（一种多重耐药细菌家族）的氨基糖苷类衍生物。 合成的AGA将进行筛选，以抑制细菌和真核生物核糖体， 抗菌活性和毒性。这些试验的结果将用于通知设计和 下一代AGA的合成。该研究的目标是提供一套经过验证的高级AGA， 对野生型和多重耐药革兰氏阴性菌显示出广泛和有效的抗生素活性， 毒性大大降低，适合未来发展。

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.