GyrB in silico mining in 27 151 global gonococcal genomes from 1928-2021 combined with zoliflodacin in vitro testing of 71 international gonococcal isolates with different GyrB, ParC and ParE substitutions confirms high susceptibility.
Por:
Golparian D, Jacobsson S, Sánchez-Busó L, Bazzo ML, Lan PT, Galarza P, Ohnishi M and Unemo M
Publicada:
23 dic 2022
Ahead of Print:
1 oct 2022
Resumen:
OBJECTIVES: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global threat and novel treatment alternatives are imperative. Herein, susceptibility to the novel antimicrobial zoliflodacin, currently in a global Phase 3 randomized controlled clinical trial for gonorrhoea treatment, was investigated by screening for zoliflodacin GyrB target mutations in publicly available gonococcal genomes and, where feasible, determination of the associated zoliflodacin MIC. METHODS: The European Nucleotide Archive was queried using the search term 'Taxon: 485'. DNA sequences from 27 151 gonococcal isolates were analysed and gyrB, gyrA, parC and parE alleles characterized. RESULTS: GyrB amino acid alterations were rare (97.0% of isolates had a wild-type GyrB sequence). GyrB V470L (2.7% of isolates) was the most prevalent alteration, followed by S467N (0.12%), N. meningitidis GyrB (0.092%), V470I (0.059%), Q468R/P (0.015%), A466T (0.0074%), L425I + L465I (0.0037%), L465I (0.0037%), G482S (0.0037%) and D429V (0.0037%). Only one isolate (0.0037%) carried a substitution in a resistance-associated GyrB codon (D429V), resulting in a zoliflodacin MIC of 8 mg/L. None of the other detected gyrB, gyrA, parC or parE mutations caused a zoliflodacin MIC outside the wild-type MIC distribution. CONCLUSIONS: The zoliflodacin target GyrB was highly conserved among 27 151 global gonococcal isolates cultured in 1928-2021. The single zoliflodacin-resistant clinical isolate (0.0037%) was cultured from a male patient in Japan in 2000. Evidently, this strain has not clonally expanded nor has the gyrB zoliflodacin-resistance mutation disseminated through horizontal gene transfer to other strains. Phenotypic and genomic surveillance, including gyrB mutations, of zoliflodacin susceptibility are imperative.
Filiaciones:
Golparian D:
Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Örebro University, Örebro, Sweden
Jacobsson S:
Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Örebro University, Örebro, Sweden
:
Genomics and Health Area, Foundation for the Promotion of Health and Biomedical Research in the Valencian Community (FISABIO-Public Health), Valencia, Spain and Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
Bazzo ML:
Molecular Biology, Microbiology and Serology Laboratory, Federal University of Santa Catarina, Florianópolis, Brazil
Lan PT:
Hanoi Medical University, National Hospital of Dermatology and Venereology, Hanoi, Vietnam
Galarza P:
National Reference Laboratory for STDs, National Institute of Infectious Diseases-ANLIS 'Dr Carlos G. Malbrán', Buenos Aires, Argentina
Ohnishi M:
Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan
Unemo M:
Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Örebro University, Örebro, Sweden
Institute for Global Health, University College London, London, UK
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