Genomic epidemiology of syphilis reveals independent emergence of macrolide resistance across multiple circulating lineages

Syphilis is an ancient sexually transmitted infection caused by the bacterium Treponema pallidum subspecies pallidum and may lead to severe clinical complications. Recent years have seen striking increases in syphilis diagnoses in many high income countries, with the UK reporting a 148% increase in new diagnoses over 10 years. The reasons for this rise are complex and multifactorial, including changing cultural, behavioural, and technological factors that influence sexual networks and transmission dynamics. Previous genomic analyses have suggested that one lineage of syphilis, called SS14, may have expanded recently, with most syphilis caused by this lineage, and that this expansion indicates emergence of a single pandemic azithromycin-resistant cluster. In this study, we used high throughput sequencing of syphilis performed on DNA extracted directly from clinical swab samples and clinically derived samples with minimal passage in the rabbit model to more than double the number of publicly available whole genome sequences. We used phylogenomic and population genomic analyses to show that both SS14-lineage and Nichols-lineage T. pallidum are present in contemporary patients and that SS14 is a polyphyletic lineage. We further correlate the appearance of genotypic macrolide resistance with multiple SS14 sub-lineages, showing that both genotypically macrolide resistant and macrolide sensitive sub-lineages are spreading contemporaneously. These findings demonstrate that macrolide resistance has independently evolved multiple times in T. pallidum, that once evolved it becomes fixed in the genome and is transmissible, and that these findings are not consistent with the hypothesis of SS14-lineage expansion purely due to macrolide resistance. Beyond relevance to our understanding of the current syphilis epidemic, these findings show how macrolide resistance evolves in Treponema subspecies. Furthermore, the evolution of macrolide resistance, despite not being first-line treatment, provides a warning on broader issues of antimicrobial resistance, and highlights the importance of stewardship and strategic planning to prevent the emergence of antimicrobial resistance.

Source: Cold Spring Harbor Laboratory

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