Formulation of molecularly-imprinted microparticles for delivery of thuricin CD to treat recurrent Clostridium difficile gut infections

用广谱抗生素治疗复发性艰难梭菌感染是常见的，但经常导致治疗结果不佳。特别是，NHS护理途径（PoC）要求抗生素按顺序给药，从效力最低的开始;至少原则上，这是为了减少对最后一线抗生素产生耐药性的机会，但在实践中，其效果是显着削弱大多数天然（共生）肠道植物群，同时产生多重耐药念珠菌。艰难菌株在这种情况下，患者通常被送入重症监护室，粪便移植是唯一剩下的治疗选择。我们的目标是通过提供thuricin CD（一种具有特异性C。与目前用于治疗C.虽然苏云金杆菌CD对艰难梭菌（例如万古霉素、甲硝唑）的抑制作用不明显，但苏云金杆菌CD不会影响胃肠道细菌的组成，有助于预防复发性感染。2然而，苏云金杆菌CD对胃中的蛋白水解和酸水解高度敏感，并且难溶于水，3因此不能以常规口服剂型递送。在这里，我们提出了一种非常有前途的方法，即使用分子印迹微粒来提供对酸和蛋白酶的保护，帮助溶解，并使肽能够完整地到达肠道。微粒将被配制在可打印的基质中，因此最终的剂型可以3D打印。这将使得肽的释放动力学能够被微调，最大化其针对C的治疗潜力。艰难感染。这项工作的主要目标是：i）分离thuricin CD; ii）开发3D打印微粒制剂; iii）在C.使用等温微量热测定法和微生物学技术在体外观察艰难梭菌的生长。

Treatment of recurrent Clostridium difficile infections with broad-spectrum antibiotics is common but frequently leads to poor treatment outcomes. In particular, the NHS Pathway of Care (PoC) requires antibiotics to be administered in a sequence, starting with the least potent; this, in principle at least, is intended to reduce the chance of resistance developing to last-line antibiotics but in practice the effect is to weaken significantly the majority of the native (commensal) gut flora while concomitantly generating a multi-drug resistant C. difficile strain. Patients in this situation are usually admitted to intensive care and faecal transplant is the only remaining treatment option. We aim to address this challenge by delivering thuricin CD (an antimicrobial peptide with specific C. difficile activity) to the gut.1 Unlike the antibiotics currently used to treat C. difficile (e.g. vancomycin, metronidazole), thuricin CD does not affect the composition of commensal gut bacteria which helps to prevent recurrent infections.2 However, it is highly susceptible to proteolysis and acid hydrolysis in the stomach, and is poorly soluble in water,3 and therefore cannot be delivered in conventional oral dosage forms. Here, we propose the highly promising approach of using molecularly-imprinted microparticles to provide protection from acid and proteases, aid solubility, and enable the peptide to reach the gut intact. The microparticles will be formulated in a printable matrix, so the final dosage forms can be 3D printed. This will enable the release kinetics of the peptide to be fine-tuned, maximising its therapeutic potential against C. difficile infections. Key aims of the work will be i) isolation of thuricin CD; ii) development of 3D-printed microparticle formulations; and iii) testing formulations on C. difficile growth in vitro using an isothermal microcalorimetric assay and microbiological techniques.