Source Tracking and Global Distribution of the Tigecycline Non-Susceptible (X).

The emergence of (X) genes has compromised the clinical use of the last-line antibiotic tigecycline. We identified 322 (1.21%) (X) positive samples from 12,829 human microbiome samples distributed in four continents (Asia, Europe, North America, and South America) using retrospective data from worldwide. These (X) genes were dominated by (X2)-like orthologs but we also identified 12 samples carrying novel (X) genes, designed (X45), (X46), and (X47), were resistant to tigecycline. The metagenomic analysis indicated these (X) genes distributed in anaerobes dominated by (78.89%) of human-gut origin. Two mobile elements IS and IS were most likely to promote the transmission of these (X2)-like orthologs between and Riemerella anatipestifer. (X2)-like orthologs was also developed during transmission by mutation to high-level tigecycline resistant genes (X45), (X46), and (X47). Further tracing these (X) in single bacterial isolate from public repository indicated (X) genes were present as early as 1960s in R. anatipestifer that was the primary (X) carrier at early stage (before 2000). The (X2) and non-(X2) orthologs were primarily distributed in humans and food animals respectively, and non-(X2) were dominated by (X3) and (X4). Genomic comparison indicated these (X) genes were likely to be generated during (X) transmission between and E. coli/Acinetobacter spp., and IS played a key role in the transmission. These results suggest R. anatipestifer was the potential ancestral source of (X). In addition, of human-gut origin was an important hidden reservoir and mutational incubator for the mobile (X) genes that enabled spread to facultative anaerobes and aerobes. The emergence of the tigecycline resistance gene (X) has posed a severe threat to public health. However, reports of its origin and distribution in human remain rare. Here, we explore the origin and distribution of (X) from large-scale metagenomic data of human-gut origin and public repository. This study revealed the emergency of (X) gene in 1960s, which has refreshed a previous standpoint that the earliest presence of (X) was in 1980s. The metagenomic analysis from data mining covered the unculturable bacteria, which has overcome the traditional bacteria isolating and purificating technologies, and the analysis indicated that the of human-gut origin was an important hidden reservoir for (X) that enabled spread to facultative anaerobes and aerobes. The continuous monitoring of mobile tigecycline resistance determinants from both culturable and unculturable microorganisms is imperative for understanding and tackling the dissemination of (X) genes in both the health care and agricultural sectors.