Abstract
BackgroundAntimicrobial resistance in Neisseria gonorrhoeae is a global health concern. Strains from two internationally circulating sequence types, ST-7363 and ST-1901, have acquired resistance to third-generation cephalosporins, mainly due to mosaic penA alleles. These two STs were first detected in Japan; however, the timeline, mechanism, and process of emergence and spread of these mosaic penA alleles to other countries remain unknown.MethodsWe studied the evolution of penA alleles by obtaining the complete genomes from three Japanese ST-1901 clinical isolates harboring mosaic penA allele 34 (penA-34) dating from 2005 and generating a phylogenetic representation of 1075 strains sampled from 35 countries. We also sequenced the genomes of 103 Japanese ST-7363 N. gonorrhoeae isolates from 1996 to 2005 and reconstructed a phylogeny including 88 previously sequenced genomes.ResultsBased on an estimate of the time-of-emergence of ST-1901 (harboring mosaic penA-34) and ST-7363 (harboring mosaic penA-10), and > 300 additional genome sequences of Japanese strains representing multiple STs isolated in 1996–2015, we suggest that penA-34 in ST-1901 was generated from penA-10 via recombination with another Neisseria species, followed by recombination with a gonococcal strain harboring wildtype penA-1. Following the acquisition of penA-10 in ST-7363, a dominant sub-lineage rapidly acquired fluoroquinolone resistance mutations at GyrA 95 and ParC 87-88, by independent mutations rather than horizontal gene transfer. Data in the literature suggest that the emergence of these resistance determinants may reflect selection from the standard treatment regimens in Japan at that time.ConclusionsOur findings highlight how antibiotic use and recombination across and within Neisseria species intersect in driving the emergence and spread of drug-resistant gonorrhea.
Highlights
Antimicrobial resistance in Neisseria gonorrhoeae is a global health concern
As shown in the 2nd column headed “continent” in Fig. 1, most strains were isolated from North America and Europe mainly through the Gonococcal Isolate Surveillance Project (GISP) [9] and the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) [13], respectively, while very few strains were isolated from Asia, Oceania, and South America
How do these estimated dates correlate to antibiotic use? there were no national data on antibiotic usage at that time in Japan, a 1999 survey on the use of antimicrobial drugs in fourteen hospitals and four clinics mostly in a prefecture in Japan showed that 50% cases exclusively used fluoroquinolones for the treatment of urethritis (Dr Mitsuru Yasuda, unpublished data)
Summary
Antimicrobial resistance in Neisseria gonorrhoeae is a global health concern. Strains from two internationally circulating sequence types, ST-7363 and ST-1901, have acquired resistance to third-generation cephalosporins, mainly due to mosaic penA alleles. These two STs were first detected in Japan; the timeline, mechanism, and process of emergence and spread of these mosaic penA alleles to other countries remain unknown. The resistance of Neisseria gonorrhoeae to thirdgeneration cephalosporins (3GCs) and fluoroquinolones has been defined as “high” priority by the World Health Organization (WHO). Many mosaic alleles have been documented, reflecting both distinct recombination events and additional mutations [7], and many of these promote resistance to 3GCs
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