From modelling to synthesis to formulation to microbe: A multi-disciplinary approach to developing treatment for multi-drug resistant respiratory infection
Arcadia Woods1, Mark Laws2, Kazi Nahar2, Shirin Jamshidi2, Charlotte Hind3, Mark Sutton3 & Khondaker Miraz Rahman2
1Medicines Development Group, School of Cancer and Pharmaceutical Sciences, King’s College London, 150 Stamford Street, London SE1 9NH, UK
2Drug Discovery Group, School of Cancer and Pharmaceutical Sciences, King’s College London, 150 Stamford Street, London SE1 9NH, UK
3 Research and Development Institute, National Infections Service, Porton Down, Public Health England, Salisbury SP4 0JG, Wiltshire, United Kingdom
Multi-drug resistant (MDR) respiratory infections represent a significant challenge for healthcare. In the race to develop new effective treatments, a multi-disciplinary approach can enable rapid development of new medicines and accelerate translation from concept to pre-clinical testing. Liposomal formulations have been widely reported to improve the efficacy of inhaled antimicrobials and may enhance the already promising activity of novel antimicrobials against challenging respiratory infections. The aim of this project was to prepare a liposomal formulation of a lead candidate novel antimicrobial molecule (AB1) and to test its antimicrobial activity against clinically relevant pathogenic species for respiratory infection.
A new antimicrobial scaffold (AB1) was synthesised following molecular modelling-led design and optimisation of a pharmacophore. Liposomes were prepared by lipid-film hydration, followed by extrusion. AB1 was loaded using the ammonium sulphate gradient method. Drug loading was quantified using high-performance liquid chromatography (HPLC) and liposome size and stability monitored using dynamic light scattering (DLS). Antimicrobial efficacy against a panel of Gram-positive strains was determined by minimum inhibitory concentration (MIC) determination.
Liposomes had a size of 140 nm and with a narrow polydispersity (P.d.I.<0.1). Liposomal-AB1 had a drug loading capacity (DLC) of 21.8%, representing ~22 mg AB1 per 100 mg formulation. AB1 retained antimicrobial activity following liposomal encapsulation against two known respiratory pathogens, Staphylococcus aureus and Enterococcus faecalis. These promising early results indicate that liposomal-AB1 is worthy of further investigation for use as an inhaled formulation, which will include in vivo efficacy studies and dosage form design.