Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases.

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.

• Authors: Gregory S Basarab, Gunther H Kern, John McNulty, John P Mueller, Kenneth Lawrence, Karthick Vishwanathan, Richard A Alm, Kevin Barvian, Peter Doig, Vincent Galullo, Humphrey Gardner, Madhusudhan Gowravaram, Michael Huband, Amy Kimzey, Marshall Morningstar, Amy Kutschke, Sushmita D Lahiri, Manos Perros, Renu Singh, Virna J A Schuck, Ruben Tommasi, Grant Walkup, Joseph V Newman
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 11827 (Jul 14 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26168713 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Anti-Bacterial Agents
• Barbiturates
• Fluoroquinolones
• Isoxazoles
• Morpholines
• Oxazolidinones
• Spiro Compounds
• Topoisomerase II Inhibitors
• DNA Topoisomerases, Type II
• zoliflodacin

Topics

• Adult
• Animals
• Anti-Bacterial Agents (chemistry, pharmacology, therapeutic use)
• Barbiturates (chemistry, pharmacology, therapeutic use)
• DNA Topoisomerases, Type II (chemistry)
• Disease Models, Animal
• Dogs
• Dose-Response Relationship, Drug
• Drug Resistance, Bacterial
• Female
• Fluoroquinolones (pharmacology)
• Gonorrhea (drug therapy, microbiology)
• Haplorhini
• Humans
• Isoxazoles
• Male
• Mice
• Microbial Sensitivity Tests
• Middle Aged
• Models, Molecular
• Molecular Conformation
• Morpholines
• Mutation
• Neisseria gonorrhoeae (drug effects, genetics)
• Oxazolidinones
• Rats
• Spiro Compounds (chemistry, pharmacology, therapeutic use)
• Staphylococcal Infections (drug therapy, microbiology)
• Staphylococcus aureus (drug effects)
• Topoisomerase II Inhibitors (chemistry, pharmacology, therapeutic use)
• Young Adult