The gonococcus and the mosaics: genomics provides further insight into a challenging landscape

As prevalence of antimicrobial-resistant Neisseria gonorrhoeae increases globally, it is important to understand the underlying trends that can contribute to this problematic issue. Whole-genome sequencing (WGS) provides much needed resolution to be able to determine key genes and mutations of interest. In The Lancet Microbe, Kim Gernert and colleagues describe a genomic analysis of N gonorrhoeae isolate surveillance data obtained in the USA in 2017.1Gernert KM Seby S Schmerer MW et al.Azithromycin susceptibility of Neisseria gonorrhoeae in the USA in 2017: a genomic analysis of surveillance data.Lancet Microbe. 2020; 1: e154-e164Summary Full Text Full Text PDF Scopus (13) Google Scholar By WGS of 410 isolates, Gernert and colleagues were able to identify the persistence and expansion of a strain associated with decreased susceptibility to azithromycin. Phylogenetic analysis showed a clade consisting of 97 isolates that harboured a mosaic mtr locus and was associated with multilocus sequence type ST9363. This clade represented nearly 70% of decreased susceptibility to azithromycin that was reported during the study period. Although it appears that this strain has persisted and gradually expanded over time, key questions remain about whether this strain could have a biological fitness advantage. These ST9363 isolates, which harbour mosaic mtr, have been previously reported in Canada2Demczuk W Martin I Peterson S et al.Genomic epidemiology and molecular resistance mechanisms of azithromycin-resistant Neisseria gonorrhoeae in Canada from 1997 to 2014.J Clin Microbiol. 2016; 54: 1304-1313Crossref PubMed Scopus (83) Google Scholar and comprise a substantial proportion of isolates that show low-level azithromycin resistance from Australia.3Williamson DA Chow EPF Gorrie CL et al.Bridging of Neisseria gonorrhoeae lineages across sexual networks in the HIV pre-exposure prophylaxis era.Nat Commun. 2019; 103988Crossref PubMed Scopus (29) Google Scholar This similarity highlights how readily N gonorrhoeae can spread from one country to another. Its presence within several countries might suggest that this strain is prevalent elsewhere; however, scant documentation reflects a paucity of surveillance in many regions. N gonorrhoeae has a well recognised ability to rapidly adapt and overcome the various antimicrobials used for its treatment. Although the gonococcus can adapt in various ways, Gernert and colleagues highlight how it can be achieved via the emergence and spread of mosaic genes, which comprise a blend of gonococcal and commensal Neisseria DNA. A notable example is the mosaic penA allele, which was first identified more than 20 years ago and is now recognised as an internationally disseminated clone4Shimuta K Watanabe Y Nakayama S et al.Emergence and evolution of internationally disseminated cephalosporin-resistant Neisseria gonorrhoeae clones from 1995 to 2005 in Japan.BMC Infect Dis. 2015; 15: 378Crossref PubMed Scopus (38) Google Scholar that has underpinned N gonorrhoeae resistance to both cefixime and ceftriaxone. The loss of ceftriaxone is especially concerning since this agent has been the mainstay of treatment for the past two decades, and there are no obvious alternatives for first-line empirical treatment. Genetic exchange and recombination within the Neisseria genus is common; however, further knowledge is needed to better understand how these mosaic sequences within key antimicrobial resistance genes emerge and are preferentially selected for. The oropharynx is a common site of infection, particularly among men who have sex with men, and it is well known that commensal Neisseria spp are ubiquitous at this site. In a study by Laumen and colleagues,5Laumen JGE Van Dijck C Abdellati S et al.Markedly reduced azithromycin and ceftriaxone susceptibility in commensal Neisseria species in clinical samples from Belgian men who have sex with men.Clin Infect Dis. 2020; (published online May 13.)https://doi.org/10.1093/cid/ciaa565Crossref PubMed Scopus (9) Google Scholar commensal Neisseria isolated from oropharyngeal swabs taken from men who have sex with men showed high minimum inhibitory concentrations for both azithromycin and ceftriaxone, thus providing a foundation for larger scale studies to investigate this area in greater detail. In the meantime, Gernert and colleagues provide a timely reminder of how WGS coupled with phenotypic surveillance can ensure that the emergence of novel resistance markers can be readily identified, and how such loci and their stability and spread through different sexual networks can be monitored via phylogenetic analyses. Moreover, we now can consider how best to use these data at a global level. Initiatives such as GISAID (the Global Initiative on Sharing all Influenza Data) has become a cornerstone for real-time data-sharing for influenza A and, since 2020, the pandemic severe acute respiratory syndrome coronavirus 2. Similar platforms are now emerging to support N gonorrhoeae surveillance at a global level, including Pathogenwatch, which was developed by the Centre for Genomic Pathogen Surveillance. This platform provides users with the ability to upload their N gonorrhoeae sequence data (in addition to other bacterial species) and, importantly, their associated metadata, to facilitate international studies and tracking of strains. Moving forward, WGS and use of international databases have considerable potential to enhance global efforts in N gonorrhoeae antimicrobial resistance, particularly if we can use these methods and resources for targeted interventions that focus on resistant strains of interest. With concerted international collaboration, perhaps we paint a better picture for the future of N gonorrhoeae antimicrobial resistance and treatment, possibly one that involves fewer mosaics. I declare no competing interests. Azithromycin susceptibility of Neisseria gonorrhoeae in the USA in 2017: a genomic analysis of surveillance dataReduced azithromycin susceptibility was associated with expanding and persistent clades harbouring two well described resistance mechanisms, mosaic mtr locus and 23S rRNA variants. Understanding the role of recombination, particularly within the mtr locus, on the fitness and expansion of strains with decreased susceptibility has important implications for the public health response to minimise gonorrhoea transmission. Full-Text PDF Open Access

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