Summary:

The National Cancer Institute (NCI) seeks licensees to further develop novel exonuclease VII (ExoVII) inhibitors as antibiotic adjuvants for enhancing the efficacy of quinolone antibiotics, particularly in quinolone-resistant bacterial infection.   

Description of Technology:

Quinolone antibiotics are a class of broad-spectrum antibiotics that act by trapping prokaryotic type IIA topoisomerases (DNA gyrase and TOPO IV), resulting in DNA damage, inhibition of DNA synthesis, and downstream bacterial death. However, current U.S. Food and Drug Administration (FDA) guidance reserves the use of quinolones for the most serious bacterial infections due to their associated side effects and to limit the occurrence of drug-resistant bacterial strains. Bacterial resistance, including to quinolone antibiotics, is a global challenge and has been dramatically increasing in incidence over the last 30 years. One mechanism of resistance to quinolone antibiotics is exonuclease VII (ExoVII). ExoVII is a well-conserved enzyme that repairs quinolone-induced DNA damage by excising the tyrosyl-DNA linkage between DNA and trapped DNA gyrase. Combination of antibiotics with antibiotic adjuvants offers a productive strategy to address the widespread emergence of antibiotic-resistant strains. However, there are currently no approved quinolone antibiotic adjuvants or drugs targeting ExoVII-mediated bacterial resistance.

Investigators in NCI’s Developmental Therapeutics Branch have discovered a family of isoquinolinedione derivatives that function as exonuclease VII (ExoVII) inhibitors that synergize with the antibacterial activity of quinolone antibiotics. In vitro, the inhibitors improved the efficacy of quinolone antibiotics and increased sensitivity to treatment of multiple bacteria strains. In quinolone-resistant bacterial strains, the co-treatment with ExoVII inhibitors reversed resistance and restored sensitivity to treatment with quinolone antibiotics. The inhibitors also exhibited no activity against the analogous repair enzyme in eukaryotes (tyrosyl DNA-phosphodiesterase 2; TDP2) and were not harmful to human cells in vitro. Overall, these inhibitors present strong potential as antibiotic adjuvants increasing the potency of quinolones, even in resistant bacterial strains.

The NCI seeks licensees to further develop these novel ExoVII inhibitors as antibiotic adjuvants for the synergistic use with quinolone antibiotics for the treatment in bacterial infections, even quinolone-resistant bacterial infections.

Potential Commercial Applications:

• Antibiotic adjuvant used in combination with ciprofloxacin and other quinolone antibiotics 
• Antibiotic adjuvant used in combination with other topoisomerase poisons

Competitive Advantages:

• Increase efficacy of quinolone antibiotics, allowing for potential antibiotic dose reduction and decreased side-effects
• Overcome ExoVII-mediated bacterial resistance to quinolone antibiotics
• Highly specific
• Potential to be first-in-class drug