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Combinatorial drug discovery in nanoliter droplets
Anthony Kulesa1,2, Jared Kehe1,2, Juan E Hurtado1,2
1Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139.
Summary
This study developed a high-throughput screening system to discover synergistic drug combinations. The system identified novel drug combinations that enhance antibiotic effectiveness against *Escherichia coli* infections.
Area of Science:
- Drug discovery and development
- Microbiology and infectious diseases
- Systems biology and network pharmacology
Background:
- Combinatorial drug treatments offer synergistic therapeutic effects but face challenges due to vast chemical space.
- Discovering novel drug combinations is crucial for advancing treatments across various diseases.
Purpose of the Study:
- To develop and apply a high-throughput nanoliter-scale phenotypic screening system for identifying synergistic drug combinations.
- To predict and validate synergistic interactions between investigational/approved drugs and antibiotics against *Escherichia coli*.
Main Methods:
- Utilized a high-throughput system for nanoliter-scale phenotypic screening using droplet emulsions.
- Automated the construction of chemical combinations en masse via parallel droplet processing.
- Screened over 4,000 drugs in combination with 10 antibiotics against *Escherichia coli*.
Main Results:
- Identified a range of drugs not previously indicated for infectious disease that exhibit synergy with antibiotics.
- Validated hits include drugs that synergize with vancomycin, erythromycin, and novobiocin against *E. coli*.
- Demonstrated the potential of non-infectious disease drugs to enhance antibiotic efficacy against gram-negative pathogens.
Conclusions:
- The developed high-throughput screening system enables efficient discovery of synergistic drug combinations.
- Novel drug combinations can overcome limitations of existing antibiotics, particularly against challenging gram-negative infections.
- This approach expands therapeutic opportunities by repurposing existing drugs for infectious disease treatment.
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