Unraveling the evolution and global transmission of high level tigecycline resistance gene tet(X)

An increasing number of tet(X) variants conferring tigecycline resistance have been reported, posing a threat to clinical treatment of multi-drug resistance bacteria as tigecycline serves as the last-resort antibiotic. In this study, a total of 721 tet(X)-like sequences were retrieved from public database and clinical isolates. All currently known tet(X) variants including newly identified variants tet(X49) to tet(X57) in our study were integrated into a database. tet(X) variants were detected in 17 countries and phylogenetically classified into 3 types: Type A, Type B and Type C, among which Type-C variants exhibited higher level tigecycline resistance. Most of Type-C variants were plasmid-mediated (65.31 %, 352/539), mainly carried by IncX1 (16.19 %, 57/352) and IncFIA/IncFIB/IncX1 (15.63 %, 55/352) plasmids. Type-C variants have achieved global spread by a two-stage expansion within 15 years. Bayesian analysis revealed that Type-C variants originated from Riemerella anatipestifer-carried Type-A variants, followed by a transfer to Escherichia and Acinetobacter strains, leading to a sharp rise of Type-C variants. Type-A variants were primarily borne in Riemerella anatipestifer and Bacteroides spp. tet(X) emerged in animal source, and gradually spread to humans and the environment. tet(X3), tet(X4) and tet(X6) were found co-occurred with more than ten antimicrobial resistance genes including bla_NDM, bla_OXA, floR, sul2, tet(M) and tet(Q). Temporal changes of transfer networks of tet(X) variants, IS elements and plasmids revealed that IS elements especially ISVsa3 facilitated the expansion of tet(X). Our findings highlight the substantial transmission risk of Type-C tet(X) variants. Persistent surveillance of the global transmission and evolutionary trend of tet(X) is essential.