Genomic evolution of  Neisseria gonorrhoeae  since the preantibiotic era (1928–2013): antimicrobial use/misuse selects for resistance and drives evolution

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Abstract

Background

Multidrug-resistant Neisseria gonorrhoeae strains are prevalent, threatening gonorrhoea treatment globally, and understanding of emergence, evolution, and spread of antimicrobial resistance (AMR) in gonococci remains limited. We describe the genomic evolution of gonococci and their AMR, related to the introduction of antimicrobial therapies, examining isolates from 1928 (preantibiotic era) to 2013 in Denmark. This is, to our knowledge, the oldest gonococcal collection globally.

Methods

Lyophilised isolates were revived and examined using Etest (18 antimicrobials) and whole-genome sequencing (WGS). Quality-assured genome sequences were obtained for 191 viable and 40 non-viable isolates and analysed with multiple phylogenomic approaches.

Results

Gonococcal AMR, including an accumulation of multiple AMR determinants, started to emerge particularly in the 1950s–1970s. By the twenty-first century, resistance to most antimicrobials was common. Despite that some AMR determinants affect many physiological functions and fitness, AMR determinants were mainly selected by the use/misuse of gonorrhoea therapeutic antimicrobials. Most AMR developed in strains belonging to one multidrug-resistant (MDR) clade with close to three times higher genomic mutation rate. Modern N. gonorrhoeae was inferred to have emerged in the late-1500s and its genome became increasingly conserved over time.

Conclusions

WGS of gonococci from 1928 to 2013 showed that no AMR determinants, except penB, were in detectable frequency before the introduction of gonorrhoea therapeutic antimicrobials. The modern gonococcus is substantially younger than previously hypothesized and has been evolving into a more clonal species, driven by the use/misuse of antimicrobials. The MDR gonococcal clade should be further investigated for early detection of strains with predispositions to develop and maintain MDR and for initiation of public health interventions.

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Most cited references 18

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Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future.

Magnus Unemo, William M. Shafer (2014)

Neisseria gonorrhoeae is evolving into a superbug with resistance to previously and currently recommended antimicrobials for treatment of gonorrhea, which is a major public health concern globally. Given the global nature of gonorrhea, the high rate of usage of antimicrobials, suboptimal control and monitoring of antimicrobial resistance (AMR) and treatment failures, slow update of treatment guidelines in most geographical settings, and the extraordinary capacity of the gonococci to develop and retain AMR, it is likely that the global problem of gonococcal AMR will worsen in the foreseeable future and that the severe complications of gonorrhea will emerge as a silent epidemic. By understanding the evolution, emergence, and spread of AMR in N. gonorrhoeae, including its molecular and phenotypic mechanisms, resistance to antimicrobials used clinically can be anticipated, future methods for genetic testing for AMR might permit region-specific and tailor-made antimicrobial therapy, and the design of novel antimicrobials to circumvent the resistance problems can be undertaken more rationally. This review focuses on the history and evolution of gonorrhea treatment regimens and emerging resistance to them, on genetic and phenotypic determinants of gonococcal resistance to previously and currently recommended antimicrobials, including biological costs or benefits; and on crucial actions and future advances necessary to detect and treat resistant gonococcal strains and, ultimately, retain gonorrhea as a treatable infection. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

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Sexually transmitted infections: challenges ahead.

Magnus Unemo, Catriona S. Bradshaw, Jane Hocking … (2017)

WHO estimated that nearly 1 million people become infected every day with any of four curable sexually transmitted infections (STIs): chlamydia, gonorrhoea, syphilis, and trichomoniasis. Despite their high global incidence, STIs remain a neglected area of research. In this Commission, we have prioritised five areas that represent particular challenges in STI treatment and control. Chlamydia remains the most commonly diagnosed bacterial STI in high-income countries despite widespread testing recommendations, sensitive and specific non-invasive testing techniques, and cheap effective therapy. We discuss the challenges for chlamydia control and evidence to support a shift from the current focus on infection-based screening to improved management of diagnosed cases and of chlamydial morbidity, such as pelvic inflammatory disease. The emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae is globally recognised. We review current and potential future control and treatment strategies, with a focus on novel antimicrobials. Bacterial vaginosis is the most common vaginal disorder in women, but current treatments are associated with frequent recurrence. Recurrence after treatment might relate to evidence that suggests sexual transmission is integral to the pathogenesis of bacterial vaginosis, which has substantial implications for the development of effective management approaches. STIs disproportionately affect low-income and middle-income countries. We review strategies for case management, focusing on point-of-care tests that hold considerable potential for improving STI control. Lastly, STIs in men who have sex with men have increased since the late 1990s. We discuss the contribution of new biomedical HIV prevention strategies and risk compensation. Overall, this Commission aims to enhance the understanding of some of the key challenges facing the field of STIs, and outlines new approaches to improve the clinical management of STIs and public health.

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Gonorrhoea

Magnus Unemo, H. Seifert, Edward Hook … (2019)

The bacterium Neisseria gonorrhoeae causes the sexually transmitted infection (STI) gonorrhoea, which has an estimated global annual incidence of 86.9 million adults. Gonorrhoea can present as urethritis in men, cervicitis or urethritis in women, and in extragenital sites (pharynx, rectum, conjunctiva and, rarely, systemically) in both sexes. Confirmation of diagnosis requires microscopy of Gram-stained samples, bacterial culture or nucleic acid amplification tests. As no gonococcal vaccine is available, prevention relies on promoting safe sexual behaviours and reducing STI-associated stigma, which hinders timely diagnosis and treatment thereby increasing transmission. Single-dose systemic therapy (usually injectable ceftriaxone plus oral azithromycin) is the recommended first-line treatment. However, a major public health concern globally is that N. gonorrhoeae is evolving high levels of antimicrobial resistance (AMR), which threatens the effectiveness of the available gonorrhoea treatments. Improved global surveillance of the emergence, evolution, fitness, and geographical and temporal spread of AMR in N. gonorrhoeae, and improved understanding of the pharmacokinetics and pharmacodynamics for current and future antimicrobials in the treatment of urogenital and extragenital gonorrhoea, are essential to inform treatment guidelines. Key priorities for gonorrhoea control include strengthening prevention, early diagnosis, and treatment of patients and their partners; decreasing stigma; expanding surveillance of AMR and treatment failures; and promoting responsible antimicrobial use and stewardship. To achieve these goals, the development of rapid and affordable point-of-care diagnostic tests that can simultaneously detect AMR, novel therapeutic antimicrobials and gonococcal vaccine(s) in particular is crucial.

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Author and article information

Contributors

Magnus Unemo:

ORCID: http://orcid.org/0000-0003-1710-2081

magnus.unemo@regionorebrolan.se

Journal

Journal ID (nlm-ta): BMC Genomics

Journal ID (iso-abbrev): BMC Genomics

Title: BMC Genomics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2164

Publication date (Electronic): 3 February 2020

Publication date PMC-release: 3 February 2020

Publication date Collection: 2020

Volume: 21

Electronic Location Identifier: 116

Affiliations

[1 ]ISNI 0000 0001 0738 8966, GRID grid.15895.30, WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, , Örebro University, ; SE-710 85 Örebro, Sweden

[2 ]Microbiotica Ltd, Biodata Innovation Centre, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK

[3 ]ISNI 0000 0004 0606 5382, GRID grid.10306.34, Centre for Genomic Pathogen Surveillance, , Wellcome Sanger Institute, ; Wellcome Genome Campus, Hinxton, Cambridgeshire, UK

[4 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Big Data Institute, Nuffield Department of Medicine, , University of Oxford, ; Oxford, UK

[5 ]ISNI 0000 0004 0417 4147, GRID grid.6203.7, Infection Preparedness, Research Unit for Reproductive Tract Microbiology, , Statens Serum Institut, ; Copenhagen, Denmark

[6 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Microbiology and Immunology and Emory Antibiotic Resistance Center, , Emory University School of Medicine, ; Atlanta, GA USA

[7 ]ISNI 0000 0004 0419 4084, GRID grid.414026.5, Laboratories of Bacterial Pathogenesis, , VA Medical Center, ; Decatur, GA USA

[8 ]ISNI 0000 0004 0606 5382, GRID grid.10306.34, Pathogen Genomics, , Wellcome Sanger Institute, ; Wellcome Genome Campus, Hinxton, Cambridgeshire, UK

Author information

Magnus Unemo http://orcid.org/0000-0003-1710-2081

Article

Publisher ID: 6511

DOI: 10.1186/s12864-020-6511-6

PMC ID: 6998845

PubMed ID: 32013864

SO-VID: 46880435-d8b8-49a0-baf0-8b191790aeb3

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 October 2019

Date accepted : 20 January 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;

Award ID: 098051

Award Recipient : Stephen D. Bentley

Funded by: Foundation for Medical Research at Örebro University Hospital

Award ID: 2012

Award Recipient : Magnus Unemo

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: neisseria gonorrhoeae,antimicrobial resistance,evolution,whole-genome sequencing,genomic epidemiology,temporal analysis

Data availability:

ScienceOpen disciplines: Genetics

Keywords: neisseria gonorrhoeae, antimicrobial resistance, evolution, whole-genome sequencing, genomic epidemiology, temporal analysis

Genomic evolution of Neisseria gonorrhoeae since the preantibiotic era (1928–2013): antimicrobial use/misuse selects for resistance and drives evolution

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Arabidopsis genomics

Most cited references 18

Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future.

Sexually transmitted infections: challenges ahead.

Gonorrhoea

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