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Zoliflodacin

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Chemical compound Pharmaceutical compound
Zoliflodacin
Clinical data
Other namesAZD0914; ETX0914
Pregnancy
category
  • Not classified yet
Routes of
administration		Oral
Drug classAntibiotic
Legal status
Legal status
Pharmacokinetic data
Bioavailability97.8%
MetabolismHepatic
Onset of action
  • Fasted: 1.5–2.3 h
  • Fed: 4 h
Elimination half-life5.3–6.3 h
Excretion
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
KEGG
Chemical and physical data
FormulaC22H22FN5O7
Molar mass487.444 g·mol
3D model (JSmol)
SMILES
  • C1CN2((O1)C)C3(CC4=C2C(=C5C(=C4)C(=NO5)N6(COC6=O)C)F)C(=O)NC(=O)NC3=O
InChI
  • InChI=1S/C22H22FN5O7/c1-8-7-33-21(32)28(8)17-12-4-11-5-22(18(29)24-20(31)25-19(22)30)16-10(3)34-9(2)6-27(16)14(11)13(23)15(12)35-26-17/h4,8-10,16H,5-7H2,1-3H3,(H2,24,25,29,30,31)/t8-,9+,10-,16+/m0/s1
  • Key:ZSWMIFNWDQEXDT-ZESJGQACSA-N

Zoliflodacin (development codes AZD0914 and ETX0914) is an experimental antibiotic that is being studied for the treatment of infection with Neisseria gonorrhoeae (gonorrhea). It has a novel mechanism of action which involves inhibition of bacterial type II topoisomerases. Zoliflodacin is being developed as part of a public-private partnership between Innoviva Specialty Therapeutics and the Global Antibiotics Research & Development Partnership (GARDP), and the drug has demonstrated clinical efficacy equivalent to ceftriaxone in Phase III clinical trials.

Susceptible bacteria

Zoliflodacin has shown in vitro activity against the following species of bacteria:

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

Compound PNU-386607, discovered in a high-throughput screen for compounds with antibiotic activity.

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. 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, 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, which was renamed Zolifodacin in the course of its clinical development.

References

  1. 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. PMID 30403954.
  2. 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. PMC 4501059. PMID 26168713.
  3. "GARDP and Innoviva Specialty Therapeutics Announce Completion of Patient Recruitment for Registrational Phase 3 Gonorrhea Treatment Trial". Innoviva Specialty Therapeutics. 23 May 2023. Retrieved 6 November 2023.
  4. "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. Retrieved 2023-11-03.
  5. 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. PMC 4501059. PMID 26168713.
  6. 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. PMC 2493097. PMID 18519725.
  7. 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. PMID 25286019.
  8. 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. PMC 4501059. PMID 26168713.
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