Chemistry:Zoliflodacin
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| Other names | AZD0914; ETX0914 |
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| Routes of administration | Oral |
| Drug class | Antibiotic |
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| Pharmacokinetic data | |
| Bioavailability | 97.8% |
| Metabolism | Hepatic |
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| Elimination half-life | 5.3–6.3 h |
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| Formula | C22H22FN5O7 |
| Molar mass | 487.444 g·mol−1 |
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Zoliflodacin (development codes AZD0914 and ETX0914) is an experimental antibiotic that is being studied for the treatment of infection with Neisseria gonorrhoeae (gonorrhea).[1] It has a novel mechanism of action which involves inhibition of bacterial type II topoisomerases.[2] Zoliflodacin is being developed by Innoviva Specialty Therapeutics, and the drug has demonstrated clinical efficacy equivalent to ceftriaxone in Phase III clinical trials.[3][4]
Susceptible bacteria
Zoliflodacin has shown in vitro activity[5] against the following species of bacteria:
- Staphylococcus aureus
- Staphylococcus pyogenes
- Streptococcus agalactiae
- Streptococcus pneumoniae
- Haemophilus influenzae
- Moraxella catarrhalis
- Mycoplasma pneumoniae
- Neisseria gonorrhoeae
- Chlamydia trachomatis
- Mycoplasma genitalium
Pharmacology
Mechanism of action
Zoliflodacin is primarily active against both Gram-positive, but has activity against fastidious Gram-negative bacteria. It functions by inhibiting DNA gyrase, an enzyme necessary to separate bacterial DNA, thereby inhibiting cell replication.
History
A high throughput screening campaign aimed at identifying compounds with whole cell antibacterial activity performed at Pharmacia & Upjohn identified compound PNU-286607, a progenitor of Zoliflodacin, as having the desired activity.[6] Subsequent biological profiling of PNU-286607 showed that the compound inhibited DNA synthesis in susceptible bacteria, and analysis of mutants resistant to the compound's activity indicated that these compounds acted on DNA gyrase at a site distinct from that of the fluoroquinolone antibiotics.
Subsequent research at AstraZeneca led to the discovery that the nitroaromatic in PNU-286607 could be replaced with a fused benzisoxazole ring,[7] which allowed for an exploration of different groups at the 3-position of the heterocycle. This work was continued at Entasis Pharmaceuticals where extensive optimization resulted in the discovery of ETX0914,[8] which was renamed Zolifodacin in the course of its clinical development.
References
- ↑ "Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea". The New England Journal of Medicine 379 (19): 1835–1845. November 2018. doi:10.1056/NEJMoa1706988. PMID 30403954.
- ↑ "Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases". Scientific Reports 5: 11827. July 2015. doi:10.1038/srep11827. PMID 26168713. Bibcode: 2015NatSR...511827B.
- ↑ "GARDP and Innoviva Specialty Therapeutics Announce Completion of Patient Recruitment for Registrational Phase 3 Gonorrhea Treatment Trial". 23 May 2023. https://innovivaspecialtytherapeutics.com/gardp-and-innoviva-specialty-therapeutics-announce-completion-of-patient-recruitment-for-registrational-phase-3-gonorrhea-treatment-trial/.
- ↑ "Positive Results Announced in Largest Pivotal Phase 3 Trial of a First-In-Class Oral Antibiotic to Treat Uncomplicated Gonorrhea" (in en-US). 2023-11-01. https://gardp.org/positive-results-announced-in-largest-pivotal-phase-3-trial-of-a-first-in-class-oral-antibiotic-to-treat-uncomplicated-gonorrhoea/.
- ↑ "Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases". Scientific Reports 5 (1): 11827. July 2015. doi:10.1038/srep11827. PMID 26168713. Bibcode: 2015NatSR...511827B.
- ↑ "Discovery and characterization of QPT-1, the progenitor of a new class of bacterial topoisomerase inhibitors". Antimicrobial Agents and Chemotherapy 52 (8): 2806–2812. August 2008. doi:10.1128/AAC.00247-08. PMID 18519725.
- ↑ "Novel DNA gyrase inhibiting spiropyrimidinetriones with a benzisoxazole scaffold: SAR and in vivo characterization". Journal of Medicinal Chemistry 57 (21): 9078–9095. November 2014. doi:10.1021/jm501174m. PMID 25286019.
- ↑ "Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases". Scientific Reports 5 (1): 11827. July 2015. doi:10.1038/srep11827. PMID 26168713. Bibcode: 2015NatSR...511827B.
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