title: Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases.
abstract: With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors. Organisms resistant to other topoisomerase inhibitors were not cross-resistant with ETX0914 nor were spontaneous resistant mutants to ETX0914 cross-resistant with other topoisomerase inhibitor classes, including the widely used fluoroquinolone class. Preclinical evaluation of ETX0914 pharmacokinetics and pharmacodynamics showed distribution into vascular tissues and efficacy in a murine Staphylococcus aureus infection model that served as a surrogate for predicting efficacious exposures for the treatment of Neisseria gonorrhoeae infections. A wide safety margin to the efficacious exposure in toxicological evaluations supported progression to Phase 1. Dosing ETX0914 in human volunteers showed sufficient exposure and minimal adverse effects to expect a highly efficacious anti-gonorrhea therapy.
authors.affiliation: Department of Chemistry, Drug Discovery and Development Center, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Basarab
authors.affiliation: AstraZeneca R&D Boston, Infection iMed, 35 Gatehouse Dr. Waltham, MA 02415 USA.
authors.forename: Gunther H
authors.initials: GH
authors.lastname: Kern
authors.affiliation: Shire Pharmaceuticals, 300 Shire Way, Lexington, MA 02421.
authors.forename: John
authors.initials: J
authors.lastname: McNulty
authors.affiliation: Entasis Therapeutics, 35 Gatehouse Drive Suite E0, Waltham, MA 02415 USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Mueller
authors.affiliation: Entasis Therapeutics, 35 Gatehouse Drive Suite E0, Waltham, MA 02415 USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lawrence
authors.affiliation: AstraZeneca R&D Boston, Infection iMed, 35 Gatehouse Dr. Waltham, MA 02415 USA.
authors.forename: Karthick
authors.initials: K
authors.lastname: Vishwanathan
authors.affiliation: AstraZeneca R&D Boston, Infection iMed, 35 Gatehouse Dr. Waltham, MA 02415 USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Alm
authors.affiliation: Albany Molecular Research Inc., 26 Corporate Circle, Albany, NY 12203.
authors.forename: Kevin
authors.initials: K
authors.lastname: Barvian
authors.affiliation: AstraZeneca R&D Boston, Infection iMed, 35 Gatehouse Dr. Waltham, MA 02415 USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Doig
authors.affiliation: AstraZeneca R&D Boston, Infection iMed, 35 Gatehouse Dr. Waltham, MA 02415 USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Galullo
authors.affiliation: AstraZeneca R&D Boston, Infection iMed, 35 Gatehouse Dr. Waltham, MA 02415 USA.
authors.forename: Humphrey
authors.initials: H
authors.lastname: Gardner
authors.affiliation: Center for Drug Evaluation and Research, U.S. FDA, 10903 New Hampshire Avenue, Silver Spring, MD 20993.
authors.forename: Madhusudhan
authors.initials: M
authors.lastname: Gowravaram
authors.affiliation: JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317.
authors.forename: Michael
authors.initials: M
authors.lastname: Huband
authors.affiliation: AstraZeneca R&D Boston, Infection iMed, 35 Gatehouse Dr. Waltham, MA 02415 USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Kimzey
authors.affiliation: Broad Institute, 415 Main St., Cambridge, MA 02142.
authors.forename: Marshall
authors.initials: M
authors.lastname: Morningstar
authors.affiliation: AstraZeneca R&D Boston, Infection iMed, 35 Gatehouse Dr. Waltham, MA 02415 USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Kutschke
authors.affiliation: AstraZeneca R&D Boston, Infection iMed, 35 Gatehouse Dr. Waltham, MA 02415 USA.
authors.forename: Sushmita D
authors.initials: SD
authors.lastname: Lahiri
authors.affiliation: Shire Pharmaceuticals, 300 Shire Way, Lexington, MA 02421.
authors.forename: Manos
authors.initials: M
authors.lastname: Perros
authors.affiliation: Department of Chemistry, Drug Discovery and Development Center, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Renu
authors.initials: R
authors.lastname: Singh
authors.affiliation: Norvartis Pharmaceutical Corporation, Bldg. 335, Office 3104B, One Health Plaza, East Hanover, NJ 07936-1080.
authors.forename: Virna J A
authors.initials: VJ
authors.lastname: Schuck
authors.affiliation: Shire Pharmaceuticals, 300 Shire Way, Lexington, MA 02421.
authors.forename: Ruben
authors.initials: R
authors.lastname: Tommasi
authors.affiliation: AstraZeneca R&D Boston, Infection iMed, 35 Gatehouse Dr. Waltham, MA 02415 USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Walkup
authors.affiliation: AstraZeneca R&D Boston, Infection iMed, 35 Gatehouse Dr. Waltham, MA 02415 USA.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Newman
mesh_terms: D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D001463:Barbiturates / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D006069:Gonorrhea / Q000188:drug therapy* / Q000382:microbiology; D000882:Haplorhini; D006801:Humans; D007555:Isoxazoles; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008958:Models, Molecular; D008968:Molecular Conformation; D009025:Morpholines; D009154:Mutation; D009344:Neisseria gonorrhoeae / Q000187:drug effects / Q000235:genetics; D023303:Oxazolidinones; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D001463:Barbiturates; D024841:Fluoroquinolones; D007555:Isoxazoles; D009025:Morpholines; D023303:Oxazolidinones; D013141:Spiro Compounds; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II; C000599190:zoliflodacin