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In vitro activity of the novel triazaacenaphthylene gepotidacin (GSK2140944) against MDR Neisseria gonorrhoeae
Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
GlaxoSmithKline, Collegeville PA, USA.
Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.ORCID iD: 0000-0003-1710-2081
2018 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 8, p. 2072-2077Article in journal (Refereed) Published
Abstract [en]

Objectives: Increased antimicrobial resistance surveillance and new effective antimicrobials are crucial to maintain treatable gonorrhoea. We examined the in vitro activity of gepotidacin, a novel triazaacenaphthylene, and the effect of efflux pump inactivation on clinical Neisseria gonorrhoeae isolates and international reference strains (n = 252) and compared gepotidacin with antimicrobials currently or previously recommended for gonorrhoea treatment.

Methods: MICs (mg/L) were determined by agar dilution (gepotidacin) or by Etest (seven other antimicrobials). The gyrA and parC genes were sequenced and the impact of inactivation of the MtrCDE, MacAB and NorM efflux pumps on gepotidacin MICs was examined.

Results: Gepotidacin showed potent in vitro activity against all gonococcal isolates (n = 252; MIC <= 4 mg/L). The modal MIC, MIC50 , MIC90 and MIC range of gepotidacin were 0.5, 0.5, 1 and 0.032-4 mg/L, respectively. Inactivation of the MtrCDE efflux pump, but not MacAB or NorM, decreased the gepotidacin MICs for most strains. No significant cross-resistance between gepotidacin and any other antimicrobials, including the fluoroquinolone ciprofloxacin, was identified. However, the ParC D86N mutation (possibly together with additional antimicrobial resistance mutation), which is associated with fluoroquinolone resistance, was associated with increased gepotidacin MICs.

Conclusions: Gepotidacin demonstrated high in vitro activity against gonococcal strains, indicating that gepotidacin could potentially be an effective option for gonorrhoea treatment, particularly in a dual antimicrobialtherapy regimen and for patients with resistance or allergy to extended-spectrum cephalosporins. Nevertheless, elucidating in vitro and in vivo resistance emergence and mechanisms in detail, together with further gonorrhoea clinical studies, ideally also including chlamydia and Mycoplasma genitalium are essential.

Place, publisher, year, edition, pages
Oxford University Press, 2018. Vol. 73, no 8, p. 2072-2077
National Category
Infectious Medicine Microbiology in the medical area Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:oru:diva-68651DOI: 10.1093/jac/dky162ISI: 000440948600009PubMedID: 29796611OAI: oai:DiVA.org:oru-68651DiVA, id: diva2:1243706
Note

Funding Agencies:

Örebro County Council Research Committee, Örebro, Sweden  

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

GlaxoSmithKline, Collegeville, PA, USA through federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority  HHSO100201300011C 

Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2018-08-31Bibliographically approved

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Jacobsson, SusanneGolparian, DanielUnemo, Magnus

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