Wellcome Trust Institutional Strategic Support Fund (ISSF) offers financial support to enhance institutional strategies for the biomedical sciences. They also provide incentives for institutions to support scientific progress, translation and interdisciplinary collaboration and to encourage greater efficiency, effectiveness and accountability in the stewardship of Wellcome Trust funding.
Supported by ISSF funding, LSTM has offered a number of competitive challenge grants to LSTM based research projects in the general area of resistance (with a focus on drugs and insecticides – RDI).
These projects will need to be completed within two years (Oct 2016).The research will focus on an area relevant to RDI, will involve PIs from more than one discipline (including external partnerships with NHS Trusts, other academic groups and industry partners), and will have the potential to generate data that can leverage further competitive research funding on completion.
The following projects have been allocated a share of joint ISSF & LSTM funding:
The rational identification of novel peroxide based antimalarial drugs that avoid the K13 mutation based resistance mechanism seen with currently deployed artemisinin based drugs
Resistance to the artemisinin-based antimalarials in S.E Asia is a serious threat to global efforts to eradicate the disease. The underlying mechanism of resistance is unknown and difficult to investigate as the phenotype cannot be readily replicated in the laboratory. However mutations in the K13 kelch like protein has been implicated. Using matched parasite isolates that have been engineered to contain either mutant or wild type K13 we will establish if the K13 linked resistance mechanism displays differential cross-resistance with a range of chemically distinct endoperoxide antimalarials. This information will enhance our understanding of the role of K13 in the resistance phenotype and will guide ongoing peroxide antimalarial drug design initiatives in Liverpool.
Evaluating the impact of insecticide resistance on the cost effectiveness of malaria control
Lead: Eve Worrall
A decision analysis model will be used to carry out generalized cost-effectiveness analysis of current and novel vector control interventions under different transmission and insecticide resistance scenarios. The output will be a user-friendly tool to enable country programmes and donors to select the optimal interventions to maintain control of resistant populations.
The project has 3 objectives:
- Gather and collate data on the cost of delivering insecticide treated nets, indoor residual spraying and other vector control interventions from recent programmes
- Estimate the public health benefit of new vector control tools using Malaria Tools software
- Develop a model to predict the cost effectiveness of different tools and determine optimal allocation of resources in the presence of different levels of insecticide resistance.
Early Prediction of the PK of Novel Endoperoxide Antimalarial Chemotherapies: A Cheminformatics Model to Predict Effective Drugs for Multidrug Resistant Plasmodium falciparum.
Lead: Raman Sharma
Endoperoxides are an intrinsic part of the first line treatment for drug-resistant malaria in the form of Artemisinin-based Combination Therapies. With emergence of Artemisinin resistance in South-East Asia there is an urgent need for the discovery and development of new endoperoxides, as these are the some of the safest, most efficacious and fast-acting of the antimalarials. Novel endoperoxides with optimal pharmacokinetics that enable the use of once-daily short treatment regimens conducive to high-compliance and high systemic drug exposures are required to overcome or mitigate against resistance. There is an unmet need to predict the PK of endoperoxides earlier in the drug discovery process, an in-silico PK prediction tool would allow de-risking of one of the major factors that is synonymous with late-stage attrition and/or emergence of resistance. In collaboration with the University of Liverpool we aim to predict preclinical pharmacokinetic parameters from the chemical structure and physicochemical properties of a library of endoperoxides through the application of QSAR/QSPR techniques in order to enable more focused endoperoxide design.
Molecular tools for insecticide resistance diagnosis in phlebotomine sandfliesfor sustainable leishmaniasis control and elimination programmes.
Lead: David Weetman
Over 60% of worldwide cases of visceral leishmaniasis (VL) cases occur in a hotspot area covering north-west India, Bangladesh and Nepal, where the sole vector is the sandfly Phlebotomus argentipes. For decades disease control has been reliant upon targeting adult sandflies by indoor residual spraying (IRS) of DDT, to which resistance is now developing. Fortunately P. argentipes appear largely susceptible to other WHO-approved insecticide classes, presenting the opportunity for effective insecticide resistance management. To realise this opportunity, and to aid VL elimination in India and beyond, a mechanistic understanding of insecticide resistance is needed to guide decision-making. To date this is lacking in any phlebotomine species and no molecular insecticide resistance diagnostics. This project, which interfaces with existing Wellcome Trust and Bill and Melinda Gates Foundation grants, will employ transcriptome sequencing and develop custom microarrays to provide knowledge and research tools for P. argentipes and assays for programmatic monitoring of resistance to insecticides of growing and future importance.
Integrating evidence-based models into serious gaming for insecticide resistance management.
Lead: Marlize Coleman
The effectiveness of many public health insecticides is on the verge of being lost as a result of increased insecticide resistance due to poor product stewardship. Looking towards the future, with new insecticides in the pipeline, there is a need to foster a more sustainable culture of public health insecticide use so that history will not be repeated. The global community understands there is a challenge, but is still unclear how individually or collectively to address this. Serious gaming is an innovative and engaging learning and communications tool that could bridge this translational gap, turning high level policy into effective operational practice.
This project aims to mobilize the vector control community and other stakeholders to obtain a comprehensive overview of key challenges faced in vector control programmes, and build the outputs of complex mathematical models of resistance management into a specification document. This will ultimately pave the way for the development of a tool that promotes best practices for insecticide resistance management, using a gaming platform that has already shown very promising results in operational settings.
Drug resistance in TB: Microbiological & pharmacological variability influencing outcomes
Lead: Derek Sloan
Drug resistant TB is a global public health problem. Current definitions of resistance are based on outdated epidemiological data from limited geographical areas and do not represent contemporary patterns of disease or therapeutic response in highly endemic countries. We will use microbiological and pharmacological data from clinical settings in Eastern Europe, Africa, Asia and South America to reassess the relationship between laboratory detection of drug-resistant TB isolates and patient outcomes. We will also use pharmacokinetic-pharmacodynamic modelling to explore how inter-individual variability in drug exposure influences patterns of drug resistance and treatment response, universally and in specific regions. This work will combine LSTM's state-of-the art laboratory facilities, multi-disciplinary skillset and diverse international research sites to generate novel data which will inform global TB control policy.
Multimeric Fc-fusion proteins: a novel approach to combat antibiotic resistant Pneumococcal disease.
Lead: Richard Pleass
The on-going Ebola outbreak has firmly cemented into the public consciousness the success and unprecedented importance of antibodies in mediating protection from dangerous pathogens. However, funding into basic research to determine how antibodies can best be engineered or repurposed for enhanced therapeutic approaches has sadly been lacking, principally because of their perceived high cost to countries that cannot afford them. With the increasing failure of drugs (especially antibiotics) and in the absence of any other therapeutic intervention that works as well as antibodies, it has become critical to investigate ways of optimizing these highly effective molecules to make them more widely available. This project therefore aims to develop novel antibody-based formats to target and clear Pneumolysin, a cholesterol-binding cytolytic toxin released during infection, with Streptococcus pneumoniae and that plays an important role in pneumococcal disease pathogenesis.
An evidence base to optimise insecticide deployment strategies in the era of resistance.
Lead: Ian Hastings
Novel and/or appropriate use of insecticides can delay, mitigate or overcome the evolution of insecticide resistance (IR). The theoretical basis for identifying optimal insecticide deployment is grossly neglected compared to our current knowledge on optimal deployment of drugs such as antimalarials and antibiotics; we intend to develop an appropriate theoretical framework to predict the spread of IR and start the process of data acquisition for their proper calibration. The project will have three principle objectives. Firstly, to implement and exploit population-genetic models of insecticide resistance (IR) to identify optimal insecticide deployment practices. Secondly, to identify how existing types of data can be used to calibrate and quantify this modelling framework. Finally, to identify novel experimental approaches to improve the evidence base upon which key insecticide deployment decisions are made.
Bringing Quality Assurance for Indoor Residual Spraying (IRS) into the 21st century: Improving IRS policy implementation to avoid and manage insecticide resistance.
Lead: Geraldine Foster
IRS is widely implemented as the mainstay of vector control interventions but is rarely performed with systematic quality assurance (QA). Until now, methods available for QA of IRS have been time-consuming and expensive; however, using the new IQK suite of tools developed by LSTM for IVCC, the concentration of insecticide delivered to wall surfaces can now be rapidly quantified in the field. Poor quality IRS leads to sub-optimal concentrations of insecticides on targeted house surfaces. There is a lack of available evidence regarding whether IRS remains operationally effective at sub-optimal insecticide concentrations and whether vector exposure to these concentrations selects for the development of insecticide resistance. The objective of this project is to develop a set of operationally tested standard operating procedures for the rigorous application of IRS QA tools for the purpose of avoiding the development of insecticide resistance.
1) To determine the sub-optimal, i.e. below the WHO recommended concentration, concentrations of insecticide at which IRS remains (partially) operationally effective on lab and wild-caught strains.
2) To develop standard operating procedures using experiences from two different contexts for the use of IRS QA tools for the avoidance of insecticide resistance.