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Tigecycline is a next\u2010generation tetracycline that is the final line of defense against severe infections by pan\u2010drug\u2010resistant bacterial pathogens. Unfortunately, this last\u2010resort antibiotic has been challenged by the recent emergence of the mobile Tet(X) orthologs that can confer high\u2010level tigecycline resistance. As it is reviewed here, these novel tetracycline destructases represent a growing threat to the next\u2010generation tetracyclines, and a basic framework for understanding the molecular epidemiology and resistance mechanisms of them is presented. 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