| 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.; Kern, Gunther H.; McNulty, John; Mueller, John P.; Lawrence, Kenneth; Vishwanathan, Karthick; Alm, Richard A.; Barvian, Kevin; Doig, Peter; Galullo, Vincent; Gardner, Humphrey; Gowravaram, Madhusudhan; Huband, Michael; Kimzey, Amy; Morningstar, Marshall; Kutschke, Amy; Lahiri, Sushmita D.; Perros, Manos; Singh, Renu; Schuck, Virna J. A.; Tommasi, Ruben; Walkup, Grant; Newman, Joseph V. |
| Source: |
Scientific Reports ; volume 5, issue 1 ; ISSN 2045-2322 |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2015 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1038/srep11827 |
| Availability: |
https://doi.org/10.1038/srep11827; https://www.nature.com/articles/srep11827; https://www.nature.com/articles/srep11827.pdf |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.D8E04E37 |
| Database: |
BASE |