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- Title
Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases.
- Authors
Basarab, Gregory S.; Singh, Renu; Kern, Gunther H.; Vishwanathan, Karthick; Alm, Richard A.; Doig, Peter; Galullo, Vincent; Gardner, Humphrey; Kimzey, Amy; Kutschke, Amy; Lahiri, Sushmita D.; Walkup, Grant; Newman, Joseph V.; McNulty, John; Perros, Manos; Tommasi, Ruben; Mueller, John P.; Lawrence, Kenneth; Barvian, Kevin; Gowravaram, Madhusudhan
- Abstract
With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.
- Subjects
GONORRHEA treatment; DNA topoisomerases; ANTIBACTERIAL agents; OXAZOLIDINONES; PHARMACODYNAMICS; THERAPEUTICS
- Publication
Scientific Reports, 2015, p11827
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/srep11827