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

在欧洲，每年有超过25,000人死于抗菌素耐药(AMR)细菌，全球的耐药率正在迅速攀升。迫切需要新型抗生素来应对抗药性细菌的崛起，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有限公司正在使用机器学习、生物信息肽设计策略和高通量生物分析来开发一种令人兴奋的新型抗菌生物制品(ABS)，专注于一种名为表皮霉素的家族。这些ABS没有已知的抵抗力，能以极低的剂量快速杀灭细菌。Amprologix目前正在开发对革兰氏阳性或革兰氏阴性AMR病原体具有特异性活性的窄谱表皮霉素。在最近的工作中，Amprologix在MRSA的关键动物感染模型中展示了我们的先导化合物表皮米星NI01的独特疗效，超过了目前的黄金标准疗法(莫匹罗星：巴曲班)；单剂NI01与6剂莫匹罗星的疗效相同。这种水平的疗效，再加上表皮霉素NI01更广泛的特性，意味着它具有极好的潜力用作预防和治疗由金黄色葡萄球菌和MRSA等细菌引起的感染的局部疗法，这些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，已被指定为高度优先的目标病原体。在医院和社区环境中，MRSA和金黄色葡萄球菌引起的感染率都在增加，对一线治疗的抵抗力也在增加。因此，迫切需要新的药物来预防和治疗由这些微生物引起的感染。在这个由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/金黄色葡萄球菌表皮霉素。我们将优化表皮霉素的配方，并在局部应用的临床前毒性评估中证明其安全性。在我们之前在可商业扩展的酵母生产系统中开发表霉素高产制造工艺的成功基础上，我们将提供符合GMP标准的预主细胞库，为生产临床级表面霉素做好准备。该项目的成功将使研究抗生素局部应用以防止MRSA感染的人类临床试验迅速发展到第一阶段。如果成功，这将降低人类使用NI01的风险，并使Amprologix能够筹集足够的风险资本，将其铅化合物推向市场，并为从同一类抗生素中开发其他“窄谱”表面霉素提供资金。最终，这将为市场带来一个强大的高效和适应性抗生素药物的新平台，极大地有利于NHS和世界各地的其他医疗保健系统。

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.