Antibiotics and anti-viral therapies have been the cornerstone of infectious disease treatment, control programs and elimination campaigns for many diseases. However, the effectiveness of existing treatments for our priority infectious diseases is increasingly compromised by the evolution of drug-resistant pathogens. We lack an understanding of the key determinants of the evolution and spread of resistance, and the ability to slow the emergence of resistant variants. Most screening approaches used currently are producing compounds that are likely to fail over time. Furthermore, combination therapies currently limit the emergence of resistance to antimicrobial agents, but even then resistance can emerge. We need new ways to create drugs that are less likely to be made ineffective by pathogen evolution, which would enhance the useful life span of resulting anti-microbial agents and reduce the frequency of treatment failures.
What We Are Looking For:
The goal of this topic is to explore new approaches that will eventually result in new therapeutics that limit the emergence of resistance, either by limiting evolutionary pressure on drug targets, blocking potential evolutionary paths or other novel mechanisms. In all cases, proposals must articulate how the emergence of drug resistance would be limited and how the likelihood for emergence of resistance could be tested. We seek proposals “off the beaten track,” significantly radical in conception, and daring in premise.
A few of the many options to be considered include:
- Novel mechanisms of action, for example targeting critical host components essential to infection and disease with little or no toxic effect on the host;
- Targeting components of the pathogen that are implicated in disease rather than infection, or that are so highly constrained that resistant variants cannot be easily selected;
- New drug leads, formulations, or delivery modalities that improve effectiveness of therapy;
- Mathematical analysis, modeling and prediction of the evolution, spread and fitness of resistant mutants during drug treatment, both within a single individual and within an epidemiological context. Explicit linkages to the discovery of new drugs must be made apparent.
For this initiative, we will not consider funding for:
- Explorations of current hypotheses unless they involve the use of technologies that have not previously been used to study the disease or pathogen;
- Proposals that simply aim to identify new targets or compounds with no regard for their capacity to generate resistance;
- Proposals for approaches that do not have a clear means of evaluating whether the target is likely to limit the emergence of resistance;
- Proposals that specifically target pathogens that cause diseases not on the foundation’s priority disease list (e.g. MRSA);
- Proposals using combinations of existing agents without regard to new mechanisms of action or new drug administrations related to drug resistance.