title: High in vitro activity of a novel dual bacterial topoisomerase inhibitor of the ATPase activities of GyrB and ParE (VT12-008911) against Neisseria gonorrhoeae isolates with various high-level antimicrobial resistance and multidrug resistance.
abstract: OBJECTIVE
  Clinical resistance to the currently recommended extended-spectrum cephalosporins (ESCs), the last remaining options for empirical antimicrobial monotherapy of gonorrhoea globally, has been reported. New antimicrobials are essential to avoid the emergence of untreatable gonorrhoea. We have investigated the in vitro activity of a novel dual bacterial topoisomerase inhibitor of the ATPase activities of GyrB and ParE (Vertex aminobenzimidazole VT12-008911), compared with antimicrobials currently or previously recommended for gonorrhoea treatment.
  
  
  METHODS
  MICs were determined using agar dilution (VT12-008911) or Etest (seven antimicrobials) for international reference strains (n = 28) and clinical Neisseria gonorrhoeae isolates (n = 220). The latter included three extensively drug-resistant isolates with high-level ceftriaxone resistance, additional isolates with clinical ESC resistance and a high number of isolates with ciprofloxacin resistance and multidrug resistance.
  
  
  RESULTS
  The MIC(50), MIC(90) and MIC range of VT12-008911 were 0.064, 0.125 and ≤0.002-0.25 mg/L, respectively. One-hundred and seventy (69%) isolates were ciprofloxacin resistant; however, only 54 of those isolates had a VT12-008911 MIC >0.064 mg/L (47 and 7 with MIC = 0.125 mg/L and MIC = 0.25 mg/L, respectively). The in vitro activity of VT12-008911 was superior to that of ciprofloxacin and all additional antimicrobials investigated. Time-kill curve analysis showed that VT12-008911 exhibited potent time-dependent bactericidal activity, at or very close to the MIC, against N. gonorrhoeae.
  
  
  CONCLUSIONS
  In vitro results suggest that VT12-008911 might be an effective treatment option for gonorrhoea. However, it will be important to detail the pharmacokinetics/pharmacodynamics, toxicity, selection and mechanisms of VT12-008911 resistance in N. gonorrhoeae and, finally, to perform well-designed in vivo randomized clinical trials.
authors.affiliation: Institute for Microbiology and Immunology, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Samo
authors.initials: S
authors.lastname: Jeverica
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Golparian
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Hanzelka
authors.affiliation: Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fowlie
authors.affiliation: Clinic for Infectious Diseases and Febrile Illnesses, University Medical Center Ljubljana, Ljubljana, Slovenia.
authors.forename: Mojca
authors.initials: M
authors.lastname: Matičič
authors.affiliation: WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden magnus.unemo@orebroll.se.
authors.forename: Magnus
authors.initials: M
authors.lastname: Unemo
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism*; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors*; D024881:Drug Resistance, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae / Q000187:drug effects* / Q000201:enzymology; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D059003:Topoisomerase Inhibitors; D000251:Adenosine Triphosphatases; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase
keywords: N. gonorrhoeae; antimicrobial treatment; ceftriaxone; gonorrhoea