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Advancing Therapeutic Discovery for Select Resistant Gram-Negative Bacteria

Biosecurity Research Programs
Image: HMS (iStock).

In response to the threat presented by increasing numbers of infections caused by antimicrobial–resistant (AR) and multidrug-resistant (MDR) Gram-negative bacterial pathogens, the NIAID Division of Microbiology and Infectious Diseases (DMID) has established research programs to facilitate development of therapeutics targeting select pathogens.

Under a new Funding Opportunity Announcement (FOA), NIAID DMID is inviting applications for milestone-driven research projects focused on development and utilization of novel predictive assays, models and/or research tools based on penetration and efflux of small molecules to facilitate therapeutic discovery for select Gram-negative bacterial pathogens: carbapenem-resistant Enterobacteriaceae (CRE), MDR Acinetobacter and/or MDR Pseudomonas aeruginosa.

The objective of this FOA is to support milestone-driven projects focused on developing and utilizing novel predictive models and/or research tools and assays aimed at gaining a better understanding of the rules and compound properties governing the penetration and efflux of drug-like small molecules into Gram-negative bacterial pathogens.

Responsive projects must focus on one or more of the following Gram-negative bacterial pathogens: carbapenem-resistant Enterobacteriaceae (CRE), MDR Acinetobacter and/or MDR Pseudomonas aeruginosa. Projects must complete assay/tool/model development prior to the end of the third year of the project period and initiate discovery activities to demonstrate its utility in supporting a corresponding medicinal chemistry program to generate a lead chemical series with demonstrated activity against one or more targeted Gram-negative bacteria.

This initiative will also support subsequent preclinical development of a promising lead antibacterial.

Examples of assay and model development include, but are not limited to:

  • Quantitative cellular (or model system) assays to measure drug penetration and efflux, independent from standard MIC testing
  • Innovative quantitative assays to measure drug concentrations in bacterial cytoplasm and/or periplasmic space
  • Innovative technologies for assessment of the kinetics of drug penetration and efflux from bacteria
  • Computational algorithms for describing/predicting physical-chemical properties or guidelines needed by small molecules for optimal Gram-negative penetration and efflux avoidance.

Successful projects will demonstrate the utility of the developed tools/assays to predict and measure potency of candidate therapeutics against Gram-negative targets. Preferably, this will be accomplished by using the developed models or assays to guide a medicinal chemistry campaign aimed at producing a novel chemical series with Gram-negative activity; or by screening existing libraries using the computational algorithms developed as a tool to find compounds with Gram-negative activity.

Alternatively, the utility of the developed tools/assays can be demonstrated by profiling existing libraries of compounds with known Gram-negative activity.

Further details are available via RFA-AI-16-081. The application deadline is May 18, 2017.

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