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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
Univ Ljubljana, Fac Med, Inst Microbiol & Immunol, Ljubljana, Slovenia..
WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Lab. Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
Vertex Pharmaceut Inc, Boston, MA USA..
Vertex Pharmaceut Inc, Boston, MA USA..
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2014 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 69, no 7, 1866-1872 p.Article in journal (Refereed) Published
Abstract [en]

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.

MICs were determined using agar dilution (VT12-008911) or Etest (seven antimicrobials) for international reference strains (naEuroS=aEuroS28) and clinical Neisseria gonorrhoeae isolates (naEuroS=aEuroS220). 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.

The MIC50, MIC90 and MIC range of VT12-008911 were 0.064, 0.125 and a parts per thousand currency sign0.002-0.25 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 MICaEuroS=aEuroS0.125 mg/L and MICaEuroS=aEuroS0.25 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.

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.

Place, publisher, year, edition, pages
Oxford University Press, 2014. Vol. 69, no 7, 1866-1872 p.
Keyword [en]
N, gonorrhoeae, gonorrhoea, antimicrobial treatment, ceftriaxone
National Category
Infectious Medicine Microbiology in the medical area Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:oru:diva-56496DOI: 10.1093/jac/dku073ISI: 000338129000019PubMedID: 24651828Scopus ID: 2-s2.0-84902491074OAI: oai:DiVA.org:oru-56496DiVA: diva2:1082451
Note

Funding Agencies:

Örebro County Council Research Committee, Örebro, Sweden

Foundation for Medical Research at Orebro University Hospital, Örebro, Sweden

Vertex Pharmaceuticals Incorporated, Boston, MA, USA

Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2017-03-16Bibliographically approved

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