Acquisition and Spread of Antimicrobial Resistance: A tet(X) Case Study

Abstract

Understanding the mechanisms leading to the rise and dissemination of antimicrobial resistance (AMR) is crucially important for the preservation of power of antimicrobials and controlling infectious diseases. Measures to monitor and detect AMR, however, have been significantly delayed and introduced much later after the beginning of industrial production and consumption of antimicrobials. However, monitoring and detection of AMR is largely focused on bacterial pathogens, thus missing multiple key events which take place before the emergence and spread of AMR among the pathogens. In this regard, careful analysis of AMR development towards recently introduced antimicrobials may serve as a valuable example for the better understanding of mechanisms driving AMR evolution. Here, the example of evolution of tet(X), which confers resistance to the next-generation tetracyclines, is summarised and discussed. Initial mechanisms of resistance to these antimicrobials among pathogens were mostly via chromosomal mutations leading to the overexpression of efflux pumps. High-level resistance was achieved only after the acquisition of flavin-dependent monooxygenase-encoding genes from the environmental microbiota. These genes confer resistance to all tetracyclines, including the next-generation tetracyclines, and thus were termed tet(X). ISCR2 and IS26, as well as a variety of conjugative and mobilizable plasmids of different incompatibility groups, played an essential role in the acquisition of tet(X) genes from natural reservoirs and in further dissemination among bacterial commensals and pathogens. This process, which took place within the last decade, demonstrates how rapidly AMR evolution may progress, taking away some drugs of last resort from our arsenal.

Tigecycline-resistant Escherichia coli ST761 carrying tet(X4) in a pig farm, China

“…Although horizontal transfer mediated by plasmids (e.g., IncQ, and IncX1) and insertion sequences (e.g., IS CR2 , IS 26 , and IS 1 ) is the main mechanism for tet (X4) transmission ( Aminov, 2021 ; Liu et al, 2022 ; Yu et al, 2022 ), clonal spread of tet (X4)-carrying strains, such as E. coli ST877, ST10, and ST48 clones is also responsible for tet (X4) dissemination between animals and humans ( Cui et al, 2022 ). The E. hormaechei co-harboring tet (X4) and bla NDM could also clonally spread from the slaughterhouse to the retail market ( Li et al, 2022 ).…”

“…However, the recent identification of novel plasmid-borne tigecycline resistance genes tet (X3) in Acinetobacter baumannii and tet (X4) in Escherichia coli from animals in China significantly impairs the clinical efficacy of tigecycline ( He et al, 2019 ). Thus far, tet (X) and its variants [ tet (X1)∼ tet (X47)] have been identified in Gram-negative pathogens and encode flavin-dependent monooxygenase that modify tigecycline ( Aminov, 2021 ; Li R. et al, 2021 ; Umar et al, 2021 ; Zhang et al, 2021 ). Among them, the mobile tet (X4) gene has been increasingly identified in E. coli from various sources including food-producing animals, wild birds, food products, humans, and the environment, mainly in China ( He et al, 2019 ; Fang et al, 2020 ; Li et al, 2020 ; Li Y. et al, 2021 ; Dong et al, 2022 ; Liu et al, 2022 ).…”

“…The heavy use of tetracyclines in animal production might facilitate the emergence and spread of tet (X) in livestock ( He et al, 2019 ). In addition, conjugative/mobilizable plasmids and mobile elements play an essential role in the dissemination of tet (X4) in Enterobacteriaceae ( Aminov, 2021 ). In this study, we aimed to investigate the prevalence and characterization of tet (X4) in E. coli isolates from one pig farm in Shanghai, China, to provide insights into the spread of tet (X4) in this swine farm.…”

Genetic Characterization of the Tetracycline-Resistance Gene tet(X) Carried by Two Epilithonimonas Strains Isolated from Farmed Diseased Rainbow Trout, Oncorhynchus mykiss in Chile

“…This is the first report of a tet (X) gene detected in pathogenic species belonging to the Flavobacteriaceae family in Chilean aquaculture and prompts the necessity to investigate the carriage of this gene by bacteria associated to Chilean salmonid farms and farmed salmonid microbiota, considering that mobilome elements such as ISCR2, IS26, and many conjugative and mobilizable plasmids could play an essential role in the acquisition and dissemination of tet (X) genes in natural reservoirs [ 54 ]. Furthermore, the potential role of pathogenic strains belonging to the Flavobacteriales occurring in Chilean salmonid farms as reservoirs of tet (X) genes must be elucidated.…”

Transferability of tigecycline resistance: Characterization of the expanding Tet(X) family

“…China has the largest waterfowl breeding industry in the world, and the massive use of antibiotics in the breeding process is inevitable. Thus, it is possible to speculate that the enrichment and differentiation of tet (X) may be related to the selective pressure brought by the large-scale use of tetracyclines in the Chinese waterfowl breeding industry (Aminov, 2021;Umar et al, 2021). This conjecture is consistent with our epidemiological surveillance, in which the tet(X) genes are prevalent in Acinetobacter of waterfowl origin, and some strains even co-carrying carbapenem resistance gene bla NDM (Cui et al, 2020;Tang, Yang, Jia, & Feng, 2021).…”