Create Drugs and Delivery Systems to Limit Drug Resistance (Round 2)

Roadblock:

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 of resistance, and the ability to slow the emergence of resistant variants. Most screening approaches in use today produce 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. While new drug discovery efforts may expand our arsenal of compounds, simply having more drugs does not address the potential emergence of resistance. We need new ways to create drugs that are less likely to be made ineffective by pathogen evolution, which would enhance the useful lifespan of 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 limit the emergence of resistance -- 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 that are “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 formulations or delivery modalities that improve the in vivo pharmacological characteristics of drugs, where a specific biological rationale exists that these improvements can limit emergence of resistance;
• Altering the inherent capacity for pathogens to evade drug sensitivity;
• 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:

• Identification of new targets or compounds with no biological rationale concerning the emergence of resistance or no clear means of evaluating whether the target, compound, or approach is likely to limit the emergence of resistance;
• Explorations of current hypotheses unless they involve the use of technologies that have not previously been used to study the disease or pathogen;
• Testing compounds against currently drug-resistant pathogens without a clear hypothesis as to why the resultant compound would be less likely to generate resistance;
• Specific targeting of pathogens that cause diseases not on the foundation’s priority disease list (e.g. MRSA);
• Community-based interventions aimed at improving adherence to drug treatment regimens;
• Use of combinations of existing agents without regard to new mechanisms of action or new drug administrations related to drug resistance.