Zoliflodacin
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Other names | AZD0914; ETX0914 |
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Routes of administration | Oral |
Drug class | Antibiotic |
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Pharmacokineticdata | |
Bioavailability | 97.8% |
Metabolism | Hepatic |
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Eliminationhalf-life | 5.3–6.3 h |
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Chemical and physical data | |
Formula | C22H22FN5O7 |
Molar mass | 487.444g·mol−1 |
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Zoliflodacin(development codesAZD0914andETX0914) is an experimentalantibioticthat is being studied for the treatment of infection withNeisseria gonorrhoeae(gonorrhea).[1]It has a novelmechanism of actionwhich involvesinhibitionof bacterialtype II topoisomerases.[2]Zoliflodacin is beingdevelopedby Innoviva Specialty Therapeutics, and the drug has demonstrated clinical efficacy equivalent toceftriaxoneinPhase III clinical trials.[3][4]
Susceptible bacteria
[edit]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
[edit]Mechanism of action
[edit]Zoliflodacin is primarily active against bothGram-positive,but has activity againstfastidiousGram-negativebacteria. It functions by inhibitingDNA gyrase,an enzyme necessary to separate bacterial DNA, thereby inhibiting cell replication.
History
[edit]![](https://upload.wikimedia.org/wikipedia/commons/thumb/0/0e/ChiralPNU.png/220px-ChiralPNU.png)
A high throughput screening campaign aimed at identifying compounds with whole cell antibacterial activity performed atPharmacia & Upjohnidentified compound PNU-286607, a progenitor of Zoliflodacin, as having the desired activity.[6]Subsequent biological profiling of PNU-286607 showed that the compound inhibitedDNA synthesisin susceptible bacteria, and analysis of mutants resistant to the compound's activity indicated that these compounds acted onDNA gyraseat a site distinct from that of thefluoroquinoloneantibiotics.
Subsequent research atAstraZenecaled to the discovery that the nitroaromatic in PNU-286607 could be replaced with a fusedbenzisoxazolering,[7]which allowed for an exploration of different groups at the 3-position of theheterocycle.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
[edit]- ^Taylor SN, Marrazzo J, Batteiger BE, Hook EW, Seña AC, Long J, et al. (November 2018)."Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea".The New England Journal of Medicine.379(19): 1835–1845.doi:10.1056/NEJMoa1706988.hdl:1805/19865.PMID30403954.
- ^Basarab GS, Kern GH, McNulty J, Mueller JP, Lawrence K, Vishwanathan K, et al. (July 2015)."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.Bibcode:2015NatSR...511827B.doi:10.1038/srep11827.PMC4501059.PMID26168713.
- ^"GARDP and Innoviva Specialty Therapeutics Announce Completion of Patient Recruitment for Registrational Phase 3 Gonorrhea Treatment Trial".Innoviva Specialty Therapeutics.23 May 2023.Retrieved6 November2023.
- ^"Positive Results Announced in Largest Pivotal Phase 3 Trial of a First-In-Class Oral Antibiotic to Treat Uncomplicated Gonorrhea".Global Antibiotic Research & Development Partnership.2023-11-01.Retrieved2023-11-03.
- ^Basarab GS, Kern GH, McNulty J, Mueller JP, Lawrence K, Vishwanathan K, et al. (July 2015)."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.Bibcode:2015NatSR...511827B.doi:10.1038/srep11827.PMC4501059.PMID26168713.
- ^Miller AA, Bundy GL, Mott JE, Skepner JE, Boyle TP, Harris DW, et al. (August 2008)."Discovery and characterization of QPT-1, the progenitor of a new class of bacterial topoisomerase inhibitors".Antimicrobial Agents and Chemotherapy.52(8): 2806–2812.doi:10.1128/AAC.00247-08.PMC2493097.PMID18519725.
- ^Basarab GS, Brassil P, Doig P, Galullo V, Haimes HB, Kern G, et al. (November 2014). "Novel DNA gyrase inhibiting spiropyrimidinetriones with a benzisoxazole scaffold: SAR and in vivo characterization".Journal of Medicinal Chemistry.57(21): 9078–9095.doi:10.1021/jm501174m.PMID25286019.
- ^Basarab GS, Kern GH, McNulty J, Mueller JP, Lawrence K, Vishwanathan K, et al. (July 2015)."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.Bibcode:2015NatSR...511827B.doi:10.1038/srep11827.PMC4501059.PMID26168713.