azd0914 has been researched along with Staphylococcal-Infections* in 3 studies
1 trial(s) available for azd0914 and Staphylococcal-Infections
| Article | Year |
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Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases.
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. Topics: Adult; Animals; Anti-Bacterial Agents; Barbiturates; Disease Models, Animal; DNA Topoisomerases, Type II; Dogs; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Female; Fluoroquinolones; Gonorrhea; Haplorhini; Humans; Isoxazoles; Male; Mice; Microbial Sensitivity Tests; Middle Aged; Models, Molecular; Molecular Conformation; Morpholines; Mutation; Neisseria gonorrhoeae; Oxazolidinones; Rats; Spiro Compounds; Staphylococcal Infections; Staphylococcus aureus; Topoisomerase II Inhibitors; Young Adult | 2015 |
2 other study(ies) available for azd0914 and Staphylococcal-Infections
| Article | Year |
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A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with
Since 2000, some thirteen quinolones and fluoroquinolones have been developed and have come to market. The quinolones, one of the most successful classes of antibacterial drugs, stabilize DNA cleavage complexes with DNA gyrase and topoisomerase IV (topo IV), the two bacterial type IIA topoisomerases. The dual targeting of gyrase and topo IV helps decrease the likelihood of resistance developing. Here, we report on a 2.8 Å X-ray crystal structure, which shows that zoliflodacin, a spiropyrimidinetrione antibiotic, binds in the same DNA cleavage site(s) as quinolones, sterically blocking DNA religation. The structure shows that zoliflodacin interacts with highly conserved residues on GyrB (and does not use the quinolone water-metal ion bridge to GyrA), suggesting it may be more difficult for bacteria to develop target mediated resistance. We show that zoliflodacin has an MIC of 4 µg/mL against Topics: Anti-Bacterial Agents; Bacteria; DNA Cleavage; DNA Gyrase; DNA Topoisomerase IV; DNA Topoisomerases, Type II; Fluoroquinolones; Humans; Microbial Sensitivity Tests; Quinolones; Staphylococcal Infections; Staphylococcus aureus; Topoisomerase II Inhibitors | 2023 |
Antibacterial Spiropyrimidinetriones with N-Linked Azole Substituents on a Benzisoxazole Scaffold Targeting DNA Gyrase.
Herein, we report spiropyrimidinetriones (SPTs) incorporating N-linked azole substituents on a benzisoxazole scaffold with improved Gram-positive antibacterial activity relative to previously described analogues. SPTs have an unusual spirocyclic architecture and represent a new antibacterial class of bacterial DNA gyrase and topoisomerase IV inhibitors. They are not cross-resistant to fluoroquinolones and other DNA gyrase/topoisomerase IV inhibitors used clinically. The activity of the SPTs was assessed for DNA gyrase inhibition, and the antibacterial activity across Gram-positive and Gram-negative pathogens with N-linked 1,2,4-triazoles substituted on the 5-position provides the most worthwhile profile. Directed nucleophilic and electrophilic chemistry was developed to vary this 5-position with carbon, nitrogen, or oxygen substituents and explore structure-activity relationships including those around a target binding model. Compounds with favorable pharmacokinetic parameters were identified, and two compounds demonstrated cidality in a mouse model of Topics: Animals; Anti-Bacterial Agents; Azoles; Disease Models, Animal; DNA Gyrase; Dose-Response Relationship, Drug; Isoxazoles; Mice; Microbial Sensitivity Tests; Molecular Structure; Pyrimidinones; Rats; Rats, Wistar; Spiro Compounds; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Topoisomerase II Inhibitors | 2020 |