Project ID CM-HD2024_52


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Institute of Pharmaceutical ScienceWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, Institute of Pharmaceutical ScienceWebsite

Development of clinically translatable drug screening platforms using in vivo models of chronic respiratory infections

Respiratory disorders, such as chronic obstructive pulmonary disease (COPD), have a high global burden of disease. Patients are predisposed to repeated bacterial lung infections, causing exacerbations and accelerating lung function decline. The emergence of antimicrobial resistance to existing antimicrobials, means infections are increasingly difficult to treat or have become ineffective entirely, highlighting an unmet clinical need for novel therapies. Animal models have been instructive in studying disease mechanisms and support pre-clinical efficacy evaluation of novel antimicrobials using biomarkers of inflammation, microbiology, and lung function. However, whilst these biomarkers (eg. FEV1 and inflammation) correlate well with human patients, they show a poorer correlation with overall clinical outcome impacting clinical translatability.

This project aims to develop more clinically translatable in vivo animal models by incorporating novel biomarkers to screen novel antimicrobials. We hypothesise these models would more sensitively evaluate drug effects and translate better to patient outcome. Our physiology team have developed a novel lung physiology biomarker called “Symmetric Project Attractor Reconstruction” (SPAR) that replots respiratory flow waveforms from resting breathing, quantifying their shape and variability. SPAR metrics more sensitively classified early lung function deterioration and inflammation, when compared to routine metrics, in animal models of respiratory disease also correlating with data from COPD patients, accessed through our NHS partners.

We are also developing novel compounds (including pleurocidin analogues) which have shown promising antimicrobial effects in vitro and in vivo. The new biomarkers will be integrated into clinically relevant respiratory infection models and used to screen both existing and novel antimicrobial agents. We predict a combination of biomarkers will more sensitively quantify lung-function deterioration following infection, and rate of recovery following treatment. We aim to identify signatures which we aim to cross validate in retrospective patient data. This is a pre-clinical drug development project aiming to advance these drugs into clinical trials.

Representative Publications

1. Platelet depletion impairs host defence to pulmonary infection with Pseudomonas aeruginosa in mice. Amison RT, O’Shaughnessy BG, Arnold S, Cleary SJ, Nandi M, Pitchford SC, Bragonzi A, Page CP. (2018). Am J Respir Cell Mol Biol. DOI: 10.1165/rcmb.2017-0083OC 2. The small quinolone derived compound HT61 enhances the effect of tobramycin against Pseudomonas aeruginosa in vitro and in vivo. Amison RT, Faure ME, O’Shaughnessy BG, Bruche KD, Hu Y, Coates A, Page CP (2020). Pulm Pharmacol Ther. DOI: 0.1016/j.pupt.2019.101884 3. A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy Manzo G, Hind CK, Ferguson PM, Amison RT, Hodgson-Casson AC, Ciazynska KA, Weller BJ, Clarke M, Lam C, Man RCH, O’Shaughnessy BG, Clifford M, Bui TT, Drake AF, Atkinson RA, Lam JKW, Pitchford SC, Page CP, Phoenix DA, Lorenz CD, Sutton JM, Mason AJ. (2020) Commun Biol. DOI: 10.1038/s42003-020-01420-3
1. Beyond HRV: attractor reconstruction using the entire cardiovascular waveform data for novel feature extraction. Aston PJ, Christie MI, Huang YH, Nandi M. (2018) Phsyiol Meas. DOI: 10.1088/1361-6579/aaa93d. 2. A novel method to quantify arterial pulse waveform morphology: attractor reconstruction for physiologists and clinicians. Nandi M, Venton J, Aston PJ. (2018). Physiol Meas. DOI: 10.1088/1361-6579/aae46a. 3. Novel breathing pattern analysis: Symmetric Projection Attractor Reconstruction (SPAR) improves identification of impending COPD reexacerbations. A retrospective cohort analysis. Pascual MS, D’Cruz R, Huang Y, Aston P, Jolley C, Rafferty G, Steier J, Nandi M. (2022) European Respiratory Journal Open Research (In press); DOI: 10.1183/13993003.congress-2022.3645