A community-driven resource for genomic surveillance of Neisseria gonorrhoeae at Pathogenwatch

Background Antimicrobial resistant (AMR) Neisseria gonorrhoeae is an urgent threat to public health, as strains resistant to at least one of the two last line antibiotics used in empiric therapy of gonorrhoea, ceftriaxone and azithromycin, have spread internationally. With new treatment options not yet available, this has prompted a call for collaborative action on global surveillance for this sexually transmitted pathogen. Whole genome sequencing (WGS) data can be used to identify new AMR clones, outbreaks, transmission networks and inform the development of point-of-care tests for antimicrobial susceptibility, novel antimicrobials and vaccines. Community driven tools that provide an easy access to and analysis of genomic and epidemiological data is the way forward for public health surveillance. Methods Here we present a public health focussed scheme for genomic epidemiology of N. gonorrhoeae using Pathogenwatch (https://pathogen.watch/ngonorrhoeae), which enables the processing of raw or assembled genomic data. We implement backwards compatibility with MLST, NG-MAST and NG-STAR typing schemes as well as an exhaustive library of genetic AMR determinants associated with resistance to eight antibiotics. A collection of over 12,000 N. gonorrhoeae genome sequences from public archives has been quality-checked, assembled and made public together with available metadata for contextualization. Results An international advisory group of experts in epidemiology, public health, genetics and genomics of N. gonorrhoeae was convened to identify public health needs in the field and inform on the utility of current and future analytics in the platform, including a customised library of genetic AMR determinants. After uploading genome data, this platform automatically provides typing information, detects genetic determinants of AMR for eight antibiotics including azithromycin and the extended-spectrum cephalosporins ceftriaxone and cefixime, and infers resistance based on the specific combination of mechanisms. Furthermore, genomes are contextualised with globally available genomic data to aid epidemiological investigation. Conclusions The N. gonorrhoeae scheme in Pathogenwatch provides customized bioinformatic pipelines guided by expert opinion that can be adapted to public health agencies and departments with little expertise in bioinformatics and lower resourced settings with internet connection but limited computational infrastructure. This advisory group will assess and identify ongoing public health needs in the field of gonococcal AMR in order to further enhance utility with modified or new analytic methods.

[1]  X. Didelot,et al.  Sudden emergence of a Neisseria gonorrhoeae clade with reduced susceptibility to extended-spectrum cephalosporins, Norway , 2020, Microbial genomics.

[2]  Tatum D. Mortimer,et al.  Increased power from conditional bacterial genome-wide association identifies macrolide resistance mutations in Neisseria gonorrhoeae , 2020, Nature Communications.

[3]  Tatum D. Mortimer,et al.  Adaptation to the cervical environment is associated with increased antibiotic susceptibility in Neisseria gonorrhoeae , 2020, Nature Communications.

[4]  Brian H. Raphael,et al.  Azithromycin susceptibility of Neisseria gonorrhoeae in the USA in 2017: a genomic analysis of surveillance data. , 2020, The Lancet. Microbe.

[5]  Tatum D. Mortimer,et al.  The Distribution and Spread of Susceptible and Resistant Neisseria gonorrhoeae Across Demographic Groups in a Major Metropolitan Center , 2020, medRxiv.

[6]  N. Low,et al.  Gonococcal vaccines: Public health value and preferred product characteristics; report of a WHO global stakeholder consultation, January 2019 , 2020, Vaccine.

[7]  D. Caugant,et al.  Genomic epidemiology and population structure of Neisseria gonorrhoeae in Norway, 2016–2017 , 2020, Microbial genomics.

[8]  Tatum D. Mortimer,et al.  Increased power from bacterial genome-wide association conditional on known effects identifies Neisseria gonorrhoeae macrolide resistance mutations in the 50S ribosomal protein L4 , 2020, bioRxiv.

[9]  K. Jolley,et al.  Association of Neisseria gonorrhoeae Plasmids With Distinct Lineages and The Economic Status of Their Country of Origin , 2020, The Journal of infectious diseases.

[10]  K. Jolley,et al.  Neisseria gonorrhoeae Population Genomics: Use of the Gonococcal Core Genome to Improve Surveillance of Antimicrobial Resistance , 2020, Journal of Infectious Diseases.

[11]  N. Field,et al.  Genomic and Phenotypic Variability in Neisseria gonorrhoeae Antimicrobial Susceptibility, England , 2020, Emerging infectious diseases.

[12]  Elizabeth A Torrone,et al.  Genomic Characterization of Neisseria gonorrhoeae Strains from 2016 U.S. Sentinel Surveillance Displaying Reduced Susceptibility to Azithromycin , 2020, Antimicrobial Agents and Chemotherapy.

[13]  M. Unemo,et al.  Genomic analysis and antimicrobial resistance of Neisseria gonorrhoeae isolates from Vietnam in 2011 and 2015–16 , 2020, The Journal of antimicrobial chemotherapy.

[14]  X. Didelot,et al.  The sudden emergence of a Neisseria gonorrhoeae strain with reduced susceptibility to extended-spectrum cephalosporins, Norway , 2020, bioRxiv.

[15]  S. Bentley,et al.  Genomic evolution of Neisseria gonorrhoeae since the preantibiotic era (1928–2013): antimicrobial use/misuse selects for resistance and drives evolution , 2020, BMC Genomics.

[16]  N. Field,et al.  Phylogenomic analysis of Neisseria gonorrhoeae transmission to assess sexual mixing and HIV transmission risk in England: a cross-sectional, observational, whole-genome sequencing study , 2020, The Lancet. Infectious diseases.

[17]  Tatum D. Mortimer,et al.  Increased antibiotic susceptibility in Neisseria gonorrhoeae through adaptation to the cervical environment , 2020, bioRxiv.

[18]  S. Sadiq,et al.  2018 UK national guideline for the management of infection with Neisseria gonorrhoeae , 2019, International journal of STD & AIDS.

[19]  Ryan R. Wick,et al.  Benchmarking of long-read assemblers for prokaryote whole , 2019 .

[20]  W. Demczuk,et al.  Equations To Predict Antimicrobial MICs in Neisseria gonorrhoeae Using Molecular Antimicrobial Resistance Determinants , 2019, Antimicrobial Agents and Chemotherapy.

[21]  A. Montgomery,et al.  Gentamicin, azithromycin and ceftriaxone in the treatment of gonorrhoea: the relationship between antibiotic MIC and clinical outcome. , 2019, The Journal of antimicrobial chemotherapy.

[22]  S. Gray-Owen,et al.  Progress Toward a Gonococcal Vaccine: The Way Forward , 2019, Front. Immunol..

[23]  K. Gernert,et al.  Genetic Similarity of Gonococcal Homologs to Meningococcal Outer Membrane Proteins of Serogroup B Vaccine , 2019, mBio.

[24]  Y. Grad,et al.  Bridging of Neisseria gonorrhoeae lineages across sexual networks in the HIV pre-exposure prophylaxis era , 2019, Nature Communications.

[25]  Rene S. Hendriksen,et al.  Using Genomics to Track Global Antimicrobial Resistance , 2019, Front. Public Health.

[26]  I. Martin,et al.  World Health Organization Global Gonococcal Antimicrobial Surveillance Program (WHO GASP): review of new data and evidence to inform international collaborative actions and research efforts. , 2019, Sexual health.

[27]  J. Corander,et al.  The impact of antimicrobials on gonococcal evolution , 2019, Nature Microbiology.

[28]  N. Low,et al.  Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016 , 2019, Bulletin of the World Health Organization.

[29]  Tatum D. Mortimer,et al.  RNA polymerase mutations cause cephalosporin resistance in clinical Neisseria gonorrhoeae isolates , 2019, bioRxiv.

[30]  Monica Lahra,et al.  Australian Gonococcal Surveillance Programme Annual Report, 2017 , 2019, Communicable diseases intelligence.

[31]  Yonatan H. Grad,et al.  Evaluation of parameters affecting performance and reliability of machine learning-based antibiotic susceptibility testing from whole genome sequencing data , 2019, bioRxiv.

[32]  V. Allen,et al.  Rationale for a Neisseria gonorrhoeae Susceptible Only Interpretive Breakpoint for Azithromycin. , 2019, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[33]  Gautam Dantas,et al.  Sequencing-based methods and resources to study antimicrobial resistance , 2019, Nature Reviews Genetics.

[34]  D. Eyre,et al.  Genetic relatedness of ceftriaxone-resistant and high-level azithromycin resistant Neisseria gonorrhoeae cases, United Kingdom and Australia, February to April 2018 , 2019, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[35]  Elizabeth A Torrone,et al.  Evidence of Recent Genomic Evolution in Gonococcal Strains With Decreased Susceptibility to Cephalosporins or Azithromycin in the United States, 2014-2016. , 2019, The Journal of infectious diseases.

[36]  Catherine D. Carrillo,et al.  ConFindr: rapid detection of intraspecies and cross-species contamination in bacterial whole-genome sequence data , 2019, PeerJ.

[37]  M. Unemo,et al.  Antimicrobial Resistance in Neisseria gonorrhoeae and Treatment of Gonorrhea. , 2019, Methods in molecular biology.

[38]  F. Balloux,et al.  From Theory to Practice: Translating Whole-Genome Sequencing (WGS) into the Clinic , 2018, Trends in microbiology.

[39]  J. Papp,et al.  The first year of the global Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) in Bangkok, Thailand, 2015-2016 , 2018, PloS one.

[40]  Michael R. Wierzbicki,et al.  Single‐Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea , 2018, New England Journal of Medicine.

[41]  W. Shafer,et al.  Mechanistic Basis for Decreased Antimicrobial Susceptibility in a Clinical Isolate of Neisseria gonorrhoeae Possessing a Mosaic-Like mtr Efflux Pump Locus , 2018, mBio.

[42]  Alexandre Souvorov,et al.  SKESA: strategic k-mer extension for scrupulous assemblies , 2018, Genome Biology.

[43]  Keith A Jolley,et al.  Open-access bacterial population genomics: BIGSdb software, the PubMLST.org website and their applications , 2018, Wellcome open research.

[44]  K. Yahara,et al.  Genomic surveillance of Neisseria gonorrhoeae to investigate the distribution and evolution of antimicrobial-resistance determinants and lineages , 2018, Microbial genomics.

[45]  M. Unemo,et al.  Gonorrhoea treatment failure caused by a Neisseria gonorrhoeae strain with combined ceftriaxone and high-level azithromycin resistance, England, February 2018 , 2018, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[46]  Monica Lahra,et al.  Genetic characterisation of Neisseria gonorrhoeae resistant to both ceftriaxone and azithromycin. , 2018, The Lancet. Infectious diseases.

[47]  Raquel Abad,et al.  Public health surveillance of multidrug-resistant clones of Neisseria gonorrhoeae in Europe: a genomic survey , 2018, The Lancet. Infectious diseases.

[48]  M. Unemo,et al.  Antimicrobial resistance and molecular epidemiology using whole-genome sequencing of Neisseria gonorrhoeae in Ireland, 2014–2016: focus on extended-spectrum cephalosporins and azithromycin , 2018, European Journal of Clinical Microbiology & Infectious Diseases.

[49]  Adrian Wensley,et al.  Sustained transmission of high-level azithromycin-resistant Neisseria gonorrhoeae in England: an observational study. , 2018, The Lancet. Infectious diseases.

[50]  Mohamad R. Abdul Sater,et al.  Azithromycin resistance through interspecific acquisition of an epistasis dependent efflux pump component and transcriptional regulator in Neisseria gonorrhoeae , 2018, bioRxiv.

[51]  M. Maiden,et al.  Identification of Novel Neisseria gonorrhoeae Lineages Harboring Resistance Plasmids in Coastal Kenya , 2018, The Journal of infectious diseases.

[52]  A. Avery,et al.  Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose-Ranging, Single-Oral Dose Evaluation , 2018, Clinical Infectious Diseases.

[53]  W. Demczuk,et al.  Cooperative Recognition of Internationally Disseminated Ceftriaxone-Resistant Neisseria gonorrhoeae Strain , 2018, Emerging infectious diseases.

[54]  N. Low Faculty Opinions recommendation of Failure of dual antimicrobial therapy in treatment of gonorrhea. , 2018 .

[55]  S. Beatson,et al.  Use of whole genome sequencing to investigate an increase in Neisseria gonorrhoeae infection among women in urban areas of Australia , 2018, Scientific Reports.

[56]  J. Kwong,et al.  Whole-genome sequencing reveals transmission of gonococcal antibiotic resistance among men who have sex with men: an observational study , 2017, Sexually Transmitted Infections.

[57]  J. Kwong,et al.  Genomic epidemiology and antimicrobial resistance of Neisseria gonorrhoeae in New Zealand , 2017, The Journal of antimicrobial chemotherapy.

[58]  J. Papp,et al.  Strengthening Global Surveillance for Antimicrobial Drug–Resistant Neisseria gonorrhoeae through the Enhanced Gonococcal Antimicrobial Surveillance Program , 2017, Emerging infectious diseases.

[59]  J. Scott,et al.  AMR Surveillance in low and middle-income settings - A roadmap for participation in the Global Antimicrobial Surveillance System (GLASS) , 2017, Wellcome open research.

[60]  R. Kirkcaldy,et al.  A Case of Decreased Susceptibility to Ceftriaxone in Neisseria gonorrhoeae in the Absence of a Mosaic Penicillin-Binding Protein 2 (penA) Allele. , 2017, Sexually transmitted diseases.

[61]  W. Demczuk,et al.  Decreased Azithromycin Susceptibility of Neisseria gonorrhoeae Isolates in Patients Recently Treated with Azithromycin , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[62]  M. Unemo,et al.  Antimicrobial resistance in Neisseria gonorrhoeae: Global surveillance and a call for international collaborative action , 2017, PLoS medicine.

[63]  Yonatan H. Grad,et al.  WGS to predict antibiotic MICs for Neisseria gonorrhoeae , 2017, The Journal of antimicrobial chemotherapy.

[64]  G. Domselaar,et al.  Neisseria gonorrhoeae Sequence Typing for Antimicrobial Resistance, a Novel Antimicrobial Resistance Multilocus Typing Scheme for Tracking Global Dissemination of N. gonorrhoeae Strains , 2017, Journal of Clinical Microbiology.

[65]  M. Maiden,et al.  Genomic analysis of urogenital and rectal Neisseria meningitidis isolates reveals encapsulated hyperinvasive meningococci and coincident multidrug-resistant gonococci , 2017, Sexually Transmitted Infections.

[66]  W. Demczuk,et al.  Decreased azithromycin susceptibility of Neisseria gonorrhoeae isolates in patients recently treated with azithromycin. , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[67]  Andrew J. Page,et al.  Multilocus sequence typing by blast from de novo assemblies against PubMLST , 2016, J. Open Source Softw..

[68]  L. Sánchez-Busó,et al.  The novel 2016 WHO Neisseria gonorrhoeae reference strains for global quality assurance of laboratory investigations: phenotypic, genetic and reference genome characterization. , 2016, The Journal of antimicrobial chemotherapy.

[69]  S. Harris,et al.  WGS analysis and molecular resistance mechanisms of azithromycin-resistant (MIC >2 mg/L) Neisseria gonorrhoeae isolates in Europe from 2009 to 2014. , 2016, The Journal of antimicrobial chemotherapy.

[70]  Daniel J. Wilson,et al.  Whole-genome sequencing to determine transmission of Neisseria gonorrhoeae: an observational study. , 2016, The Lancet. Infectious diseases.

[71]  Anna G. Green,et al.  Genomic Epidemiology of Gonococcal Resistance to Extended-Spectrum Cephalosporins, Macrolides, and Fluoroquinolones in the United States, 2000–2013 , 2016, The Journal of infectious diseases.

[72]  Stephen D. Bentley,et al.  Genomic Analysis and Comparison of Two Gonorrhea Outbreaks , 2016, mBio.

[73]  M. Unemo,et al.  Failure of Dual Antimicrobial Therapy in Treatment of Gonorrhea. , 2016, The New England journal of medicine.

[74]  J. Kwong,et al.  NGMASTER: in silico multi-antigen sequence typing for Neisseria gonorrhoeae , 2016, bioRxiv.

[75]  G. Horsman,et al.  Genomic Epidemiology and Molecular Resistance Mechanisms of Azithromycin-Resistant Neisseria gonorrhoeae in Canada from 1997 to 2014 , 2016, Journal of Clinical Microbiology.

[76]  Brian D. Ondov,et al.  Mash: fast genome and metagenome distance estimation using MinHash , 2015, Genome Biology.

[77]  N. Loman,et al.  Twenty years of bacterial genome sequencing , 2015, Nature Reviews Microbiology.

[78]  Ulf Schaefer,et al.  An outbreak of high-level azithromycin resistant Neisseria gonorrhoeae in England , 2015, Sexually Transmitted Infections.

[79]  Andrew J. Page,et al.  Roary: rapid large-scale prokaryote pan genome analysis , 2015, bioRxiv.

[80]  C. del Rio,et al.  Population structure of Neisseria gonorrhoeae based on whole genome data and its relationship with antibiotic resistance , 2015, PeerJ.

[81]  A. Amato-Gauci,et al.  Risk Factors for Antimicrobial-Resistant Neisseria gonorrhoeae in Europe , 2014, Sexually transmitted diseases.

[82]  B. Langmead,et al.  Lighter: fast and memory-efficient sequencing error correction without counting , 2014, Genome Biology.

[83]  G. Horsman,et al.  Whole-Genome Phylogenomic Heterogeneity of Neisseria gonorrhoeae Isolates with Decreased Cephalosporin Susceptibility Collected in Canada between 1989 and 2013 , 2014, Journal of Clinical Microbiology.

[84]  M. Unemo,et al.  Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future , 2014, Clinical Microbiology Reviews.

[85]  S. Solomon,et al.  Antibiotic resistance threats in the United States: stepping back from the brink. , 2014, American family physician.

[86]  Björn Usadel,et al.  Trimmomatic: a flexible trimmer for Illumina sequence data , 2014, Bioinform..

[87]  Julian Parkhill,et al.  Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study , 2014, The Lancet. Infectious diseases.

[88]  M. Unemo,et al.  The European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP)—a sentinel approach in the European Union (EU)/European Economic Area (EEA) , 2013, Sexually Transmitted Infections.

[89]  Magnus Unemo,et al.  Identification of Amino Acids Conferring High-Level Resistance to Expanded-Spectrum Cephalosporins in the penA Gene from Neisseria gonorrhoeae Strain H041 , 2013, Antimicrobial Agents and Chemotherapy.

[90]  Alexey A. Gurevich,et al.  QUAST: quality assessment tool for genome assemblies , 2013, Bioinform..

[91]  M. Unemo,et al.  Evolution of Neisseria gonorrhoeae is a continuing challenge for molecular detection of gonorrhoea: false negative gonococcal porA mutants are spreading internationally , 2012, Sexually Transmitted Infections.

[92]  M. Unemo,et al.  Neisseria gonorrhoeae Strain with High-Level Resistance to Spectinomycin Due to a Novel Resistance Mechanism (Mutated Ribosomal Protein S5) Verified in Norway , 2012, Antimicrobial Agents and Chemotherapy.

[93]  Sergey I. Nikolenko,et al.  SPAdes: A New Genome Assembly Algorithm and Its Applications to Single-Cell Sequencing , 2012, J. Comput. Biol..

[94]  Matthew Berriman,et al.  Artemis: an integrated platform for visualization and analysis of high-throughput sequence-based experimental data , 2011, Bioinform..

[95]  M. Unemo,et al.  High-Level Cefixime- and Ceftriaxone-Resistant Neisseria gonorrhoeae in France: Novel penA Mosaic Allele in a Successful International Clone Causes Treatment Failure , 2011, Antimicrobial Agents and Chemotherapy.

[96]  Steven Salzberg,et al.  BIOINFORMATICS ORIGINAL PAPER , 2004 .

[97]  M. Unemo,et al.  Review and International Recommendation of Methods for Typing Neisseria gonorrhoeae Isolates and Their Implications for Improved Knowledge of Gonococcal Epidemiology, Treatment, and Biology , 2011, Clinical Microbiology Reviews.

[98]  M. Unemo,et al.  Is Neisseria gonorrhoeae Initiating a Future Era of Untreatable Gonorrhea?: Detailed Characterization of the First Strain with High-Level Resistance to Ceftriaxone , 2011, Antimicrobial Agents and Chemotherapy.

[99]  Magnus Unemo,et al.  Molecular and structural analysis of mosaic variants of penicillin-binding protein 2 conferring decreased susceptibility to expanded-spectrum cephalosporins in Neisseria gonorrhoeae: role of epistatic mutations. , 2010, Biochemistry.

[100]  S. Chisholm,et al.  High-Level Azithromycin Resistance Occurs in Neisseria gonorrhoeae as a Result of a Single Point Mutation in the 23S rRNA Genes , 2010, Antimicrobial Agents and Chemotherapy.

[101]  Magnus Unemo,et al.  Genetics of Chromosomally Mediated Intermediate Resistance to Ceftriaxone and Cefixime in Neisseria gonorrhoeae , 2009, Antimicrobial Agents and Chemotherapy.

[102]  Douglas M. Warner,et al.  Clinically relevant mutations that cause derepression of the Neisseria gonorrhoeae MtrC‐MtrD‐MtrE Efflux pump system confer different levels of antimicrobial resistance and in vivo fitness , 2008, Molecular microbiology.

[103]  Neisseria gonorrhoeae multi-antigen sequence typing (NG-MAST) of ciprofloxacin resistant isolates of Pretoria, South Africa , 2007, Journal of Clinical Pathology.

[104]  K. Jolley,et al.  Species status of Neisseria gonorrhoeae: evolutionary and epidemiological inferences from multilocus sequence typing , 2007, BMC Biology.

[105]  Roberta J. Lindberg,et al.  Neisseria gonorrhoeae Isolates with Reduced Susceptibility to Cefixime and Ceftriaxone: Association with Genetic Polymorphisms in penA, mtrR, porB1b, and ponA , 2007, Antimicrobial Agents and Chemotherapy.

[106]  W. Shafer,et al.  Characterization of the MacA-MacB efflux system in Neisseria gonorrhoeae. , 2005, The Journal of antimicrobial chemotherapy.

[107]  C. Davies,et al.  High-Level Chromosomally Mediated Tetracycline Resistance in Neisseria gonorrhoeae Results from a Point Mutation in the rpsJ Gene Encoding Ribosomal Protein S10 in Combination with the mtrR and penB Resistance Determinants , 2005, Antimicrobial Agents and Chemotherapy.

[108]  J. Jorgensen,et al.  Mutations in folP Associated with Elevated Sulfonamide MICs for Neisseria meningitidis Clinical Isolates from Five Continents , 2005, Antimicrobial Agents and Chemotherapy.

[109]  Kevin A Fenton,et al.  Rapid sequence-based identification of gonococcal transmission clusters in a large metropolitan area. , 2004, The Journal of infectious diseases.

[110]  W. Whittington,et al.  Acquired Macrolide Resistance Genes in Pathogenic Neisseria spp. Isolated between 1940 and 1987 , 2003, Antimicrobial Agents and Chemotherapy.

[111]  W. Shafer,et al.  The NorM Efflux Pump of Neisseria gonorrhoeae and Neisseria meningitidis Recognizes Antimicrobial Cationic Compounds , 2003, Journal of bacteriology.

[112]  W. Whittington,et al.  Acquired macrolide resistance genes and the 1 bp deletion in the mtrR promoter in Neisseria gonorrhoeae. , 2003, The Journal of antimicrobial chemotherapy.

[113]  W. Shafer,et al.  Overexpression of the MtrC-MtrD-MtrE Efflux Pump Due to an mtrR Mutation Is Required for Chromosomally Mediated Penicillin Resistance in Neisseria gonorrhoeae , 2002, Journal of bacteriology.

[114]  B. Wretlind,et al.  Mutations in gyrA, gyrB, parC, and parE in quinolone‐resistant strains of Neisseria gonorrhoeae , 2002, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[115]  L. Ng,et al.  Mutation in 23S rRNA Associated with Macrolide Resistance in Neisseria gonorrhoeae , 2002, Antimicrobial Agents and Chemotherapy.

[116]  M. Hobbs,et al.  Identification and Analysis of Amino Acid Mutations in Porin IB That Mediate Intermediate-Level Resistance to Penicillin and Tetracycline in Neisseria gonorrhoeae , 2002, Antimicrobial Agents and Chemotherapy.

[117]  P. A. Ropp,et al.  Mutations in ponA, the Gene Encoding Penicillin-Binding Protein 1, and a Novel Locus, penC, Are Required for High-Level Chromosomally Mediated Penicillin Resistance in Neisseria gonorrhoeae , 2002, Antimicrobial Agents and Chemotherapy.

[118]  I. Martin,et al.  GRASP: a new national sentinel surveillance initiative for monitoring gonococcal antimicrobial resistance in England and Wales , 2001, Sexually transmitted infections.

[119]  W. Whittington,et al.  Identification of the Conjugative mefGene in Clinical Acinetobacter junii and Neisseria gonorrhoeae Isolates , 2000, Antimicrobial Agents and Chemotherapy.

[120]  D. E. Roe,et al.  Erythromycin-Resistant Neisseria gonorrhoeae and Oral Commensal Neisseria spp. Carry Known rRNA Methylase Genes , 1999, Antimicrobial Agents and Chemotherapy.

[121]  I. Kobayashi,et al.  Development of fluoroquinolone resistance and mutations involving GyrA and ParC proteins among Neisseria gonorrhoeae isolates in Japan. , 1998, The Journal of urology.

[122]  W. Shafer,et al.  Missense mutations that alter the DNA-binding domain of the MtrR protein occur frequently in rectal isolates of Neisseria gonorrhoeae that are resistant to faecal lipids. , 1995, Microbiology.

[123]  T. Ezaki,et al.  DNA gyrase mutations in quinolone-resistant clinical isolates of Neisseria gonorrhoeae , 1995, Antimicrobial agents and chemotherapy.

[124]  W. M. Huang,et al.  Neisseria gonorrhoeae acquires mutations in analogous regions of gyrA and parC in fluoroquinolone‐resistant isolates , 1994, Molecular microbiology.

[125]  K. Holmes,et al.  National surveillance of antimicrobial resistance in Neisseria gonorrhoeae , 1990, JAMA.

[126]  M. Ehrenberg,et al.  Ribosomal RNA and protein mutants resistant to spectinomycin. , 1990, The EMBO journal.

[127]  B. Spratt Hybrid penicillin-binding proteins in penicillin-resistant strains of Neisseria gonorrhoeae , 1988, Nature.

[128]  S. Morse,et al.  High-level tetracycline resistance in Neisseria gonorrhoeae is result of acquisition of streptococcal tetM determinant , 1986, Antimicrobial Agents and Chemotherapy.

[129]  T F Mroczkowski,et al.  [Penicillinase-producing Neisseria gonorrhoeae]. , 1977, Przeglad dermatologiczny.

[130]  V. Hemming,et al.  PENICILUNASE-PRODUCING NEISSERIA GONORRHŒÆ , 1976, The Lancet.

[131]  Robin Sibson,et al.  SLINK: An Optimally Efficient Algorithm for the Single-Link Cluster Method , 1973, Comput. J..

[132]  AustrAliAn GonococcAl surveillAnce ProGrAmme AnnuAl rePort , 2022 .