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

Rustam Aminov

doi:10.3390/ijms22083905

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.

Highlights

In 2009, I analysed the phylogeny of relatively few tet(X) genesdiscovered at that time, which belong to the A family of flavin-dependent monooxygenases (FMOs) which are widely distributed in a variety of natural microbiota [2]
The risk of horizontal transfer of this non-specific resistance nodulation division (RND) resistance machinery among bacterial pathogens is low because they belong to the core constituents of bacterial genomes, they are complex, and they have evolved to perform a variety of specific functions within the cell other than antimicrobial resistance
It has been concluded that the above prerequisites could make FMOs/Tet Xs the most likely mechanisms for the emergence of a high-level resistance to third-generation tetracyclines among bacterial pathogens

Summary

Introduction

In 2009, I analysed the phylogeny of relatively few tet(X) genes (spelling of tetracyclineresistant determinants in this article follows the nomenclature by Levy and others [1]). Several tet(X) variants that are located on plasmids and confer high level resistance to the next-generation tetracyclines, tigecycline, eravacycline and omadacycline, can be found in human and animal isolates of Acinetobacter species, including A. baumannii [15,19,22,28]. Acquisition and dissemination of these tet(X) variants was mediated via ISCR2 and IS26 transposition into a variety of conjugative and mobilizable plasmids belonging to different incompatibility groups Transfer of these tet(X)-bearing plasmids into A. baumannii strains circulating in the hospital environment may lead to the failure of therapies by drugs of last resort such as the next-generation tetracyclines. The role of conjugative transposons and ICEs in the dissemination of tet(X) seems less prominent compared to the plasmid-mediated HGT

Emergence and Rise of AMR

Findings

Conclusions