title: Characterization of the novel DNA gyrase inhibitor AZD0914: low resistance potential and lack of cross-resistance in Neisseria gonorrhoeae.
abstract: The unmet medical need for novel intervention strategies to treat Neisseria gonorrhoeae infections is significant and increasing, as rapidly emerging resistance in this pathogen is threatening to eliminate the currently available treatment options. AZD0914 is a novel bacterial gyrase inhibitor that possesses potent in vitro activities against isolates with high-level resistance to ciprofloxacin and extended-spectrum cephalosporins, and it is currently in clinical development for the treatment of N. gonorrhoeae infections. The propensity to develop resistance against AZD0914 was examined in N. gonorrhoeae and found to be extremely low, a finding supported by similar studies with Staphylococcus aureus. The genetic characterization of both first-step and second-step mutants that exhibited decreased susceptibilities to AZD0914 identified substitutions in the conserved GyrB TOPRIM domain, confirming DNA gyrase as the primary target of AZD0914 and providing differentiation from fluoroquinolones. The analysis of available bacterial gyrase and topoisomerase IV structures, including those bound to fluoroquinolone and nonfluoroquinolone inhibitors, has allowed the rationalization of the lack of cross-resistance that AZD0914 shares with fluoroquinolones. Microbiological susceptibility data also indicate that the topoisomerase inhibition mechanisms are subtly different between N. gonorrhoeae and other bacterial species. Taken together, these data support the progression of AZD0914 as a novel treatment option for the oral treatment of N. gonorrhoeae infections.
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA richard.alm@astrazeneca.com sushmita.lahiri@astrazeneca.com.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Alm
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA richard.alm@astrazeneca.com sushmita.lahiri@astrazeneca.com.
authors.forename: Sushmita D
authors.initials: SD
authors.lastname: Lahiri
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Kutschke
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Linda G
authors.initials: LG
authors.lastname: Otterson
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: McLaughlin
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Whiteaker
authors.affiliation: UMass Medical School, Worcester, Massachusetts, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lewis
authors.affiliation: Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, People's Republic of China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Su
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Huband
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: Humphrey
authors.initials: H
authors.lastname: Gardner
authors.affiliation: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Mueller
mesh_terms: D001463:Barbiturates / Q000494:pharmacology*; D027081:DNA Gyrase / Q000737:chemistry / Q000235:genetics; D024881:Drug Resistance, Bacterial; D007555:Isoxazoles; D008826:Microbial Sensitivity Tests; D009025:Morpholines; D009154:Mutation; D009344:Neisseria gonorrhoeae / Q000187:drug effects* / Q000235:genetics; D023303:Oxazolidinones; D013141:Spiro Compounds / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D001463:Barbiturates; D007555:Isoxazoles; D009025:Morpholines; D023303:Oxazolidinones; D013141:Spiro Compounds; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase; C000599190:zoliflodacin