- Kevin Chang
Topoisomerase poisons, such as quinolone antibiotics, are widely used as anticancer drugs and antibiotics. Quinolone antibiotics act by trapping prokaryotic type IIA topoisomerases (DNA gyrase and TOPO IV), resulting in irreversible topoisomerase cleavage complexes. 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. Resistance to available antibiotics in pathogenic bacteria is a global challenge as the number of drug-resistant strains increased dramatically each year.
Combination of antibiotics with antibiotic adjuvants offers a productive strategy to address the widespread emergence of antibiotic-resistant strains. Exonuclease VII (ExoVII) repairs quinolone-induced DNA damage by excising the tyrosyl-DNA linkage between DNA and trapped DNA gyrase, an essential prokaryotic type II A topoisomerase. Consequently, inactivation of ExoVII results in hypersensitivity to quinolones. Researchers at the NCI have discovered ExoVII inhibitors that synergize with the antimicrobial activity of the quinolone antibiotic ciprofloxacin. These inhibitors present strong potential as antibiotic adjuvants increasing the potency of quinolones – particularly against quinolone-resistant bacterial strains. In addition, the combination of ExoVII inhibitors with quinolones may allow dose reduction – potentially decreasing side-effects.
The NCI seeks co-development partners or licensees to further develop the novel ExoVII inhibitor(s) as antibiotic adjuvants for enhancing the efficacy of quinolone antibiotics, particularly in quinolone-resistant bacterial strains.
- Antibiotic adjuvant in combination with ciprofloxacin and other quinolone antibiotics
- Antibiotic adjuvant in combination with other topoisomerase poisons
- ExoVII inhibitor increases the efficacy of quinolone antibiotics, allowing dose reduction for quinolones and potentially decrease side-effects and be well-tolerated
- Potentially overcome bacterial resistance to quinolones
- Lack of inhibitory activity against human tyrosyl-DNA phosphodiesterase (TDP) suggests that inhibitors targeting prokaryotic ExoVII might decrease side-effects and be well-tolerated
Yves Pommier MD PhD (NCI), Shar-yin Naomi Huang PhD (NCI), Brianna B Mitchell BS (NCI)
- Pre-clinical (in vivo)
Huang SN, et al. Exonuclease VII repairs quinolone-induced damage by resolving DNA gyrase cleavage complexes. [PMID 33658195]
- U.S. Provisional: U.S. Provisional Patent Application Number 63/129,217, Filed 22 Dec 2020
- Infectious Diseases