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Plasmid Transfer Let Cholera Pathogen in Yemen Become Multidrug Resistant, Study Suggests

NEW YORK – New research suggests that mobile genetic elements (MGEs) moving between cholera-causing Vibrio cholerae pathogens and non-pathogenic environmental strains have contributed to the advent of multidrug-resistant (MDR) microbes involved in an outbreak in Yemen.

"The emergence of this MDR pathogen demonstrates the necessity of continued genomic surveillance of the microbial population associated with the ongoing Yemen cholera outbreak, and of new outbreaks that may take place in regionally connected areas," first author Florent Lassalle, a researcher with the Wellcome Sanger Institute's Parasites and Microbes Program, and colleagues wrote in Nature Microbiology on Thursday.

"Such surveillance will enable Yemeni public health authorities to rapidly adapt clinical practices to minimize [antimicrobial resistance] selective pressures," they explained. "This also warrants increased efforts in research on the molecular mechanisms and evolution of interactions between MGEs, to learn about the constraints ruling their colonization of bacterial genomes."

For the analysis, researchers at the Wellcome Sanger Institute, Sana'a University in Yemen, the Pasteur Institute, and other international centers generated 281 whole-genome sequences from 260 V. cholerae isolates collected during the outbreak in 2018 and 2019.

The team noted that a surveillance system operated under Yemen's public health and population ministry has identified roughly 2.4 million potential cholera cases between 2016, when the cholera outbreak began, and August 2019 — an epidemic driven in part by geopolitical events in the country and their impact on individuals living there.

"Since 2016, Yemen has seen the largest epidemic of cholera ever recorded," the authors explained. "This occurred against the backdrop of a civil war turned international conflict and famine, which together fueled extensive population movement, with more than 4 million people internally displaced by the end of 2020."

With the new genome sequences, coupled with insights from nearly 900 V. cholerae sequences in public genome databases and phylogenetic analyses, the team saw signs of recombination between epidemic versions of V. cholerae with the so-called "7PET" genotype and non-7PET genotype, non-cholera-causing strains.

This mixing introduced an MDR-related resistance plasmid that has persisted in the 7PET strain, the authors explained, leading to ramped-up resistance to macrolide-based antibiotics such as erythromycin and azithromycin that have been used to treat severe cases of cholera, particularly in children and pregnant women affected by the outbreak.

"These patient demographics created unique conditions for natural selection of antibiotic resistance in the cholera pathogen: The acquisition of a plasmid — an additional bit of DNA — by the epidemic strain conferred it resistance to multiple drugs, and led it to take over as the dominant pathogen in the Yemen outbreak," Lassalle said in an email, noting that children under the age of 15 make up roughly one-third of cholera cases identified in the outbreak.

In contrast to sequence-swapping events detected in the past, which led to transient recombination events, the current results pointed to maintenance of the drug resistance plasmid in the 7PET V. cholerae genotype over long stretches of time, he explained, consistent with the emergence of a new form of cholera that is both multidrug resistant and highly transmissible.

Such results have implications for treating severe cholera cases that arise during the Yemen outbreak, the authors reported, while highlighting the importance of continuing to track V. cholerae genetics and spread in that country and beyond.

"This new epidemic multidrug-resistant cholera has so far only been seen in Yemen, but could spread further," Lassalle suggested. "This warrants continued epidemic surveillance in this region and globally, using genomic techniques to identify what strains are causing disease and to understand how they are related."