Pre-clinical validation of a potent candidate in the fight against AMR HCAI

在欧洲，抗微生物药物耐药性（AMR）细菌每年杀死2.5万多人，世界范围内的耐药性正在迅速攀升。迫切需要新型抗生素来应对抗生素耐药细菌的增加，并作为衍生化、多样化和增强疗效的支架，这一策略在青霉素等前几代药物中被证明是成功的。Amprologix有限公司正在利用机器学习、生物信息学肽设计策略和高通量生物测定技术，开发一种令人兴奋的新型抗菌生物制剂（ABs），主要围绕表皮霉素家族。这些抗体没有已知的耐药性，在非常低的剂量下就能迅速杀死细菌。Amprologix目前正在开发窄谱表皮蛋白酶，对革兰氏阳性或革兰氏阴性AMR病原体具有特异性活性。在最近的研究中，Amprologix在一个关键的MRSA动物感染模型中显示，我们的先导化合物表皮霉素NI01比目前的金标准疗法（莫匹罗星：Bactroban）有独特的益处；单剂NI01与6剂莫匹罗星一样有效。这种疗效水平，加上表皮霉素NI01的更广泛的特性，意味着它在预防和治疗由金黄色葡萄球菌和MRSA等细菌引起的感染方面具有极好的潜力，这两种细菌是欧洲皮肤和软组织感染的主要原因。MRSA也是英国和欧洲医疗保健相关感染（HCAI）的主要原因之一，已被指定为高优先级目标病原体。在医院和社区环境中，MRSA和金黄色葡萄球菌引起的感染率正在上升，对一线治疗的耐药性正在增加。因此，迫切需要新的药物来预防和治疗由这些生物体引起的感染。在这个sbri资助的项目中，Amprologix将快速跟踪NI01的临床前开发，NI01是第一种抗mrsa /S药物。球菌epidermicin。我们将优化表皮蛋白的配方，并在局部应用的临床前毒性评估中证明其安全性。基于我们之前在商业化可扩展的酵母生产系统中成功开发表皮细胞素抗生素高产生产工艺的基础上，我们将提供符合GMP的预主细胞库，准备生产临床级表皮细胞素。该项目的成功将使研究抗生素局部应用以预防MRSA感染的第一阶段人体临床试验迅速进展。如果成功，这将降低NI01用于人类的风险，并允许Amprologix筹集足够的风险资本，将其主要化合物推向市场，并资助从同类抗生素中开发其他“窄谱”表皮蛋白。最终，这将为市场带来一个强大的高效和适应性强的抗生素药物新平台，极大地惠及NHS和全球其他医疗保健系统。

Antimicrobial resistant (AMR) bacteria kill over 25,000 people a year in Europe and resistance rates are climbing rapidly worldwide. There is a critical need for novel classes of antibiotics to tackle the rise of antibiotic resistant bacteria and serve as scaffolds for derivatisation, diversification and enhancement of efficacy, a strategy proven successful with previous generations of drugs such as penicillin. Amprologix Ltd is using machine learning, bioinformatic peptide design strategies and high-throughput biological assays to develop an exciting new class of antimicrobial biologics (ABs) focused around a family called epidermicins. These ABs have no known resistance liabilities and rapidly kill bacteria at very low doses. Amprologix is currently developing narrow-spectrum epidermicins that are specifically active against either Gram positive or Gram-negative AMR pathogens. In recent work, Amprologix has shown unique benefits of epidermicin NI01, our lead compound, over current gold-standard therapy (mupirocin: Bactroban) in a key animal infection model for MRSA; a single dose of NI01 was as effective as six doses of mupirocin. This level of efficacy, combined with the broader properties of epidermicin NI01 mean it has excellent potential for use as a topical therapy for prevention and treatment of infections caused by bacteria like Staphylococcus aureus and MRSA, which are leading causes of skin and soft tissue infections in Europe. MRSA is also one of the leading causes of healthcare associated infections (HCAI) in the UK and Europe and has been designated as a high priority target pathogen. In both hospital and community settings, the rate of infections caused by MRSA and S. aureus are increasing and resistance to front-line therapies is growing. Consequently, there is an urgent need for new agents to prevent and treat infection caused by these organisms. In this SBRI-funded project, Amprologix will fast-track the pre-clinical development of NI01, the first anti-MRSA/S. aureus epidermicin. We will optimise the formulation of epidermicin and demonstrate its safety in a pre-clinical evaluation of toxicity in a topical application. Building on our previous successes in developing a high-yield manufacturing process for epidermicin antibiotics in a commercially-scalable yeast production system, we will deliver a GMP compliant pre-master cell bank, ready for manufacture of clinical grade epidermicin. Success in this project will allow rapid progression to a phase-1 human clinical trial investigating the topical application of the antibiotic to prevent MRSA infections. If successful, this will de-risk NI01 for human use and allow Amprologix to raise sufficient venture capital to bring its lead compound to market and fund the development of other 'narrow spectrum' epidermicins from the same class of antibiotics. Ultimately this will bring a powerful new platform of highly effective and adaptable antibiotic drugs to market, greatly benefiting the NHS and other healthcare systems worldwide.