CEIDR TPP fund: Successful projects

Lead identification of new pyrazolopyrimidinenes for the treatment of multi-drug-resistant (MDR) tuberculosis (TB)

Prof. Giancarlo Biagini, Liverpool School of Tropical Medicine; Collaborators: University of Liverpool and Eisai Ltd

The investigating team has identified novel compounds (pyrazolopyrimidines) with in vitro activity against Mycobacterium tuberculosis (Mtb) and favourable drug-like (DMPK) properties.  In this CEIDR award, we wish to undertake further work to determine the efficacy of this class of inhibitors in additional models of Mtb infection.  In addition, a more detailed structure-activity relationship (SAR) study of the pyrazolopyrimidines will be undertaken using both existing in-house and newly synthesised pyrazolopyrimidines tested against a number of Mtb in vitro assays including MDR Mtb clinical isolates.  This is a unique opportunity to de-risk a TB drug discovery project and thereby making it attractive and competitive for follow-on funding.  The work is directly aligned to LSTM's strategy of translational research in infectious diseases of LMICs and UoLs strategic focus in infectious diseases.

Attenuated Total Reflection Fourier transform infrared (ATR-FTIR) spectroscopy point-of-care testing for the detection of sepsis pathogens.

Prof. Enitan Carrol, University of Liverpool, Biotech Resources; Collaborators: Alder Hey Children’s Hospital and Monash University

Rapid detection of sepsis pathogens direct from blood: Sepsis is a life-threatening disease that results in the deaths of over 6 million people every year. Rapid detection is essential to save lives. In this study, we will use the technique called Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy on blood from patients with sepsis to detect the bacteria causing sepsis. The instrument passes infrared light through the sample and the reflected light measured by a spectrometer. Results are obtained within minutes. If we can demonstrate that this can be done accurately, then it could be applied directly to blood from patients as a rapid bedside test for sepsis.

The PneumEx Study: Experimental Human Pneumococcal Challenge and Exhaled Pneumococcal Biomarkers

Dr. Andrea Collins, Liverpool School of Tropical Medicine; Collaborators: University Hospital Aintree/Royal Liverpool and Broadgreen University Hospital, University College London, University of Warwick and IMSPEX Diagnostics Ltd

Exploring the use of exhaled breath testing to improve the diagnosis of respiratory tract infections:

Even with in-depth testing we frequently fail to identify the cause of a patient’s pneumonia. This study investigates the use of two new techniques that use the exhaled breath to try and improve this. The first is ‘BreathSpec’, which can identify small quantities of exhaled compounds that are produced by bacteria and second is the ‘Exhaled Detection Facemask’ which is used to grow bacteria from samples collected while breathing out. We are investigating whether these devices are able to identify the bacteria pneumococcus, the leading cause of pneumonia globally, as part of the Liverpool EHPC (Experimental Human Pneumococcal Challenge) programme.

Development of novel experimental models to explore the Dose-Exposure-Response relationships of therapeutics with activity against Neisseria gonorrhoeae

Dr. Shampa Das, University of Liverpool; Collaborators: Liverpool School of Tropical Medicine and University of Liverpool, Summit Therapeutics and Bugworks Research Inc

Experimental models to support the development of therapeutics targeting Gonorrhoea:

Antibiotic-resistant gonorrhea is a developing and serious threat, with reported cases of “super gonorrhea” which is resistant to currently used antibiotics. The WHO has prioritised Neisseria gonorrhea as a pathogen for which new antibiotics are needed. Whilst new drugs are being developed, there are no experimental models to explore the dose-exposure-response relationship which is pivotal for dose selection. Correct dose selection is essential to ensure that the new antibiotic is efficacious and also does not encounter issues with drug resistance. The aim of this work is to develop novel experimental model systems to explore drug-resistant gonorrhea. 

Development of smart molecules for tracking insecticides from surface to target

Dr Mark Paine, Liverpool School of Tropical Medicine; Collaborator: University of Liverpool

The control of malaria and other insect-transmitted diseases relies on the use of insecticide-treated materials. Exactly how insecticides are presented on surfaces and taken up by insects is still poorly understood. This project will develop smart molecules and apply state-of-the-art surface chemistry to visually track insecticides from the surface to the insect target.  This will transform our understanding of how insecticide-treated materials work and support the development of safer, more effective products for disease control with minimal effect on beneficial organisms and the environment.

Click-chemistry to enhance the therapeutic efficacy and translational potential of the IgG1-

Prof. Richard Pleass, Liverpool School of Tropical Medicine; Collaborators: the University of Liverpool and CSL Behring

Many pathogens of global importance including viruses and parasites have a strict requirement for sialic acid-binding to infect human tissues. Exploiting this essential requirement to develop small molecule inhibitors has met with limited success, principally because the strong interaction between the pathogen and host cells requires multivalent binding to sialic acid. We will take a click-chemistry approach to a clinically proven and well understood therapeutic, the antibody molecule, to remodel sialic acids for enhanced blocking of pathogens. This approach will also bring improvements to antibodies that target non-infectious diseases e.g. cancer, that underpins a multi-billion-pound global industry.

Validation of novel anti-Wolbachia chemotypes as heartworm preventatives

Dr. Joe Turner, Liverpool School of Tropical Medicine; Collaborators: the University of Liverpool and Eisai Inc.

Anti-Wolbachia chemical compounds as potential new heartworm drugs:

Heartworm is a filarial nematode infection of cats, dogs, and humans. The identification of drug resistance in heartworm jeopardizes heartworm disease control, a veterinary market worth ~$500 million annually. A new approach to anti-filarial treatment is targeting filarial endosymbiotic bacteria, Wolbachia with antibiotics. The Anti-Wolbachia consortium has screened ~2.5 million novel compounds and identified multiple unique small molecules with superior anti-Wolbachia activities compared to registered antibiotics. In this pump-priming project, we will test selected anti-Wolbachia small molecules against heartworm larvae to identify chemicals that can deplete Wolbachia following as little as 48-hour exposure-time frame. Data generated will be used in support of external industry collaboration grant applications to develop novel anti-Wolbachia candidates for heartworm.