Development of a novel parasite-derived peptide for the treatment of chronic bacterial lung infection and inflammation

Context The development of novel antimicrobial treatments that could directly regulate bacterial load and growth in the lung (chronic infection) would revolutionise the lives of patients with lung diseases such as chronic obstructive pulmonary disease (COPD) and Cystic Fibrosis (CF) lung disease by sustaining and maintaining lung function. Additionally, antimicrobial agents that can act by inducing a robust host-derived antibacterial response (immunotherapeutics) may also circumvent the issue of antimicrobial resistance. Helminth parasites such as Fasciola hepatica are masters of immune regulation – they can survive for many years in their host by selectively suppressing or modulating specific arms of their host immune systems by secreting specific proteins (e.g. F. hepatica host defence molecule-1, FhHDM-1). We have synthesised and identified a novel derivative of FhHDM-1, called FhHDM-1 NT, which displays potent antibacterial effects in vitro and in vivo, similar to the parent peptide and with novel IP (intellectual property). FhHDM-1 NT activates host cells, such as macrophages, to remove bacteria more efficiently by a mechanism that is partly dependent on the activation of a macrophage kinase pathway. In this project, we will investigate the ability of the NT peptide to be delivered directly to the lungs of infected mice and retain its antibacterial activity against prominent lung disease-causing bacterial pathogens such as Pseudomonas aeruginosa and Haemophilus influenzae. This study will provide proof of principle data for a future DPFS application which will evaluate direct nebulised delivery of the NT peptide in vivo in collaboration with respiratory CROs Aims and objectives Can FhHDM-1 NT peptide be instilled directly into the lung and retain its antibacterial activity? Does lung instilled FhHDM-1 NT peptide alter lung inflammation in vivo? Potential applications and benefits There is currently a lack of effective immunotherapies that are capable of reducing bacterial infection via a mechanism that activates the lung host defence system. Antibiotics, steroids and bronchodilators are routinely used as therapies in COPD but have little or no value in fully eliminating bacteria from the lungs of patients or reducing inflammation in these conditions. These patients are also susceptible to pulmonary exacerbations and, due to the rise of antibiotic resistance, there is a need for novel, effective and safe therapeutics that can promote bacterial clearance and control inflammation. It is well-known that periods of exacerbation result in decreased lung function, which is thought to emanate from the damage caused by infection-induced inflammation during this period. Treatments that can effectively clear infection may successfully impact on subsequent inflammation and lung damage and may limit disease progression. The interest in peptides as drugs is growing rapidly because of the ease and relatively low cost of synthesis while direct instillation into the lung will be an attractive delivery option for these peptides