Developing Strathclyde minor groove binders as Novel Gram-negative active drugs

开发 Strathclyde 小沟结合剂作为新型革兰氏阴性活性药物

• 批准号: 2432472
• 金额: --
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2432472
• 关键词: Developing; Strathclyde; minor; groove; binders

Urgent action is required to develop novel antimicrobials to treat multidrug resistant bacterial infections. Without this, we risk slipping into a "post-antibiotic era" where a cut or simple operation is a life-threatening event, such as they were before the discovery of penicillin. Of particular concern is the lack of novel compounds for the treatment of Gram-negative bacteria, which are inherently more challenging due to the difficulty that antibiotics have in penetrating their cell envelope. Furthermore, the inherent ability of Gram-negative bacteria to induce efflux pumps that actively remove the antibiotic from the cell is another obstacle. These difficulties conspire to make Gram-negative bacteria a fundamentally challenging arena for antibacterial drug discovery.New antibiotics are needed now, yet it is well-established that at least 7-10 years are required to develop a drug. One way to mitigate this delay is to take advantage of work in progress, hence the significance of this research: one compound from our drug discovery platform, MGB-BP-3, has entered Phase IIa clinical trials in Q1 2019 for treatment of Clostridium difficile infections.[5] This proposal seeks to reduce the threat of Gram-negative pathogens through the comprehensive investigation of strategies to adapt an exclusively Gram-positive active class of antibiotic, Strathclyde Minor Groove Binders (S-MGB), towards treatment of Gram-negative infections. Significantly, the Strathclyde Minor Groove Binder project is currently one of the Department of Pure and Applied Chemistry's and SIPBS's Impact Case Studies for REF2021; this project seeks to sustain the impact of this project for both Departments, ready for the next REF.There already exists a variety of strategies that have been successfully applied to current exclusively Gram-positive active drug classes, extending their use to Gram-negative infections. The most significant problem with these strategies is that they have been applied to antibiotic classes that have already seen extensive use in the clinic: resistance will quickly develop, rendering these efforts futile. The goal of this research proposal is to apply these established strategies to our novel class of antibiotic, S-MGBs, to impart activity against Gram-negative organisms. The project is thus of minimal risk as these strategies have already been demonstrated to be successful. Moreover, not only is there an absence of an established reservoir of resistance to MGBs, but we have been unable to raise resistant mutants against bacteria when challenged with serial passaging. Proposed is an ambitious and comprehensive strategy with which to achieve this goal. Specifically, it will: (i) fully investigate the synergistic combinations of S-MGBs with efflux pump inhibitors, antimicrobial peptides, cell permeabilising agents, and existing antibiotics; (ii) select the best synergy partners and covalently tether them to MGBs yielding novel MGB-conjugates; however, we propose to go beyond simple conjugation by (iii) developing more drug-like S-MGB-hybrids, which contain the smallest set of structural features necessary for activity. Significantly, we will have access to the expertise and facilities at Public Health England for the duration of this project.Ultimately, compounds of significant activity will enter into our development pipeline with our industry partner MGB Biopharma.

迫切需要采取行动，开发新的抗菌药物来治疗多重耐药细菌感染。如果不这样做，我们就有可能滑入一个“后抗生素时代”，在这个时代，一个割伤或简单的手术都是危及生命的事件，就像青霉素发现之前一样。特别令人担忧的是缺乏用于治疗革兰氏阴性菌的新型化合物，由于抗生素难以穿透其细胞包膜，因此这些革兰氏阴性菌本质上更具挑战性。此外，革兰氏阴性菌诱导主动从细胞中去除抗生素的外排泵的固有能力是另一个障碍。这些困难使革兰氏阴性菌成为抗菌药物发现的一个具有根本挑战性的竞技场。现在需要新的抗生素，但众所周知，开发一种药物至少需要7-10年。缓解这种延迟的一种方法是利用正在进行的工作，因此这项研究的重要性：我们的药物发现平台MGB-BP-3的一种化合物已于2019年第一季度进入IIa期临床试验，用于治疗艰难梭菌感染。[5]该提案旨在通过全面调查策略来减少革兰氏阴性病原体的威胁，以适应专门的革兰氏阳性活性抗生素类，Strathclyde小沟粘合剂（S-MGB），用于治疗革兰氏阴性感染。值得注意的是，斯特拉斯克莱德小沟粘结剂项目目前是纯粹和应用化学系和SIPBS的REF 2021影响案例研究之一;该项目旨在维持该项目对两个部门的影响，为下一个REF做好准备。已经存在各种各样的策略，这些策略已经成功地应用于当前唯一的革兰氏阳性活性药物类别，将它们的用途扩展到革兰氏阴性感染。这些策略最重要的问题是，它们已应用于已经在临床上广泛使用的抗生素类别：耐药性将迅速发展，使这些努力徒劳无功。本研究提案的目标是将这些既定策略应用于我们的新型抗生素S-MGB，以赋予针对革兰氏阴性菌的活性。因此，该项目的风险很小，因为这些战略已被证明是成功的。此外，不仅缺乏对MGBs的已建立的抗性库，而且当用连续传代挑战时，我们也无法产生针对细菌的抗性突变体。为实现这一目标，提出了一项雄心勃勃的全面战略。具体而言，它将：（i）充分研究S-MGB与外排泵抑制剂、抗微生物肽、细胞透化剂和现有抗生素的协同组合;然而，我们建议通过（iii）开发更多药物样S-MGB-杂合体，其包含活性所需的最小结构特征集。值得注意的是，在项目期间，我们将获得英国公共卫生部的专业知识和设施。最终，具有重要活性的化合物将进入我们与行业合作伙伴MGB Biofilma的开发管道。