Zoliflodacin

Zoliflodacin
Clinical data
Other names	AZD0914; ETX0914
Pregnancy; category	Not classified yet;
Routes of; administration	Oral
Drug class	Antibiotic
Legal status
Legal status	US: Investigational New Drug; Investigational;
Pharmacokinetic data
Bioavailability	97.8%
Metabolism	Hepatic
Onset of action	Fasted: 1.5–2.3 h; Fed: 4 h;
Elimination half-life	5.3–6.3 h
Excretion	Faeces (79.6%); Urine (18.2%);
Identifiers
CAS Number	1620458-09-4;
PubChem CID	76685216;
DrugBank	12817;
UNII	FWL2263R77;
KEGG	D11726;
Chemical and physical data
Formula	C22H22FN5O7
Molar mass	487.444 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C[C@@H]1CN2[C@H]([C@@H](O1)C)C3(CC4=C2C(=C5C(=C4)C(=NO5)N6[C@H](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).^[1] It has a novel mechanism of action which involves inhibition of bacterial type II topoisomerases.^[2] Zoliflodacin is being developed as part of a public-private partnership between Innoviva Specialty Therapeutics and the Global Antibiotic Research & Development Partnership (GARDP), 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:

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.^[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

^ 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.
^ 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.
^ "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.
^ "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.
^ 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.
^ 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.
^ 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.
^ 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.

[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.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]