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

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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.