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

需要采取紧急行动，开发新的抗微生物药物来治疗耐多药细菌感染。如果没有这一点，我们就有可能滑入“后抗生素时代”，在这个时代，伤口或简单的手术都是危及生命的事件，就像在发现青霉素之前一样。特别值得关注的是缺乏治疗革兰氏阴性菌的新化合物，由于抗生素难以穿透其细胞包膜，革兰氏阴性菌本身就更具挑战性。此外，革兰氏阴性菌诱导外排泵主动从细胞中清除抗生素的固有能力是另一个障碍。这些困难共同使革兰氏阴性菌成为抗菌药物发现的一个根本挑战。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年的时间。缓解这种延迟的一种方法是利用正在进行的工作，因此这项研究具有重要意义：我们药物发现平台的一种化合物MGB-BP-3已于2019年第一季度进入治疗艰难梭菌感染的ii期临床试验本提案旨在通过全面研究革兰氏阴性病原体的威胁，以适应一种完全革兰氏阳性活性抗生素，Strathclyde Minor Groove binder (S-MGB)，用于治疗革兰氏阴性感染。值得注意的是，Strathclyde Minor Groove Binder项目目前是纯粹与应用化学系和SIPBS的REF2021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，为下一届reff做好准备。已经存在各种战略，已成功应用于目前的革兰氏阳性活性药物类别，将其应用于革兰氏阴性感染。这些策略最重要的问题是，它们被应用于已经在临床中广泛使用的抗生素类别：耐药性将迅速发展，使这些努力无效。这项研究计划的目标是将这些既定的策略应用于我们的新型抗生素s - mgb，以赋予抗革兰氏阴性菌的活性。由于这些策略已经被证明是成功的，因此该项目的风险很小。此外，不仅缺乏对mgb的抗性储存库，而且在连续传代的挑战下，我们无法培养抗细菌的抗性突变体。提出了一项雄心勃勃的全面战略，以实现这一目标。具体来说，它将：(i)充分研究S-MGBs与外排泵抑制剂、抗菌肽、细胞渗透剂和现有抗生素的协同组合；（ii）选择最佳协同合作伙伴，并将其共价连接到mgb上，产生新的mgb偶联物；然而，我们建议通过（iii）开发更多类似药物的s - mgb杂交体来超越简单的偶联，这些杂交体包含活性所需的最小结构特征集。值得注意的是，在本项目期间，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与我们的行业合作伙伴MGB Biopharma一起进入我们的开发管道。

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.