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;
Pharmacokineticdata
Bioavailability	97.8%
Metabolism	Hepatic
Onset of action	Fasted: 1.5–2.3 h; Fed: 4 h;
Eliminationhalf-life	5.3–6.3 h
Excretion	Faeces(79.6%); Urine(18.2%);
Identifiers
CAS Number	1620458-09-4;
PubChemCID	76685216;
DrugBank	12817;
UNII	FWL2263R77;
KEGG	D11726;
Chemical and physical data
Formula	C22H22FN5O7
Molar mass	487.444g·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 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

Zoliflodacin has shown in vitro activity^[5]against the following species of bacteria:

Pharmacology

Mechanism of action

Zoliflodacin is primarily active against bothGram-positive,but has activity againstfastidious Gram-negativebacteria. It functions by inhibitingDNA 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 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

^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.PMC4501059.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.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.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.PMC2493097.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.PMC4501059.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.PMC4501059.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.Retrieved6 November2023.

[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.Retrieved2023-11-03.

[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.PMC4501059.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.PMC2493097.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.PMC4501059.PMID 26168713.

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