Dissecting the molecular evolution of fluoroquinolone resistant Shigella sonnei

Shigella sonnei increasingly dominates the epidemiological landscape of shigellosis globally, with treatment options dwindling due to resistance to several key antimicrobials, particularly the fluoroquinolones. Here we compiled nearly 400 S. sonnei whole genome sequences from both endemic and non-endemic regions to delineate the evolutionary history of the recently emerging fluoroquinolone resistant S. sonnei. We reaffirm that extant resistant organisms belong to a single clonal expansion event. Sequential accumulation of defining mutations (gyrA-S83L, parC-S80I, and gyrA-D87G) led to the emergence of the fluoroquinolone resistant S. sonnei population around the year 2007 in South Asia. This clone then was transmitted globally, resulting in establishments in Southeast Asia and Europe. Detailed mutation analysis predicts that the clone became dominant through enhanced adaptation to oxidative stress. Experimental evolution revealed that under fluoroquinolone exposure in vitro, resistant S. sonnei developed further intolerance to the antimicrobial while the susceptible counterpart failed to attain complete resistance.