Tetracycline-inactivating enzymes from environmental, human commensal, and pathogenic bacteria cause broad-spectrum tetracycline resistance

Abstract

Tetracycline resistance by antibiotic inactivation was first identified in commensal organisms but has since been reported in environmental and pathogenic microbes. Here, we identify and characterize an expanded pool of tet(X)-like genes in environmental and human commensal metagenomes via inactivation by antibiotic selection of metagenomic libraries. These genes formed two distinct clades according to habitat of origin, and resistance phenotypes were similarly correlated. Each gene isolated from the human gut encodes resistance to all tetracyclines tested, including eravacycline and omadacycline. We report a biochemical and structural characterization of one enzyme, Tet(X7). Further, we identify Tet(X7) in a clinical Pseudomonas aeruginosa isolate and demonstrate its contribution to tetracycline resistance. Lastly, we show anhydrotetracycline and semi-synthetic analogues inhibit Tet(X7) to prevent enzymatic tetracycline degradation and increase tetracycline efficacy against strains expressing tet(X7). This work improves our understanding of resistance by tetracyclineinactivation and provides the foundation for an inhibition-based strategy for countering resistance.

Identification of novel tetracycline resistance gene tet (X14) and its co-occurrence with tet (X2) in a tigecycline-resistant and colistin-resistant Empedobacter stercoris

“…It therefore is reasonable to raise the concern that Tet(X) family tigecycline resistance determinants are with potential large-scale dissemination. Indeed, a most recent study dramatically extends the members of Tet (X) family from 7 to 14 [14,15,23]. This study highlights that numerous Tet(X) variants have already circulated in various environmental ecosystem.…”

“…Plasmid-mediated tet(X3), tet(X3.2), tet(X4), tet(X5) and tet(X6) have been detected in A. baumannii, Empedobacter brevis, E. falsenii, A. indicus, A. schindleri, A. lwoffiiand and A. towneri isolated from chickens, pigs, cattle, shrimp, avian and human [16][17][18][19][20][21][22]. Most recently, another 7 variants including tet(X7) to tet(X13) have been detected in 244 gut-derived metagenomic libraries in America [23]. Of concern, Tet(X4) and Tet(X6) have recently been found to co-exist with mcr-1 in E. coli [24,25].…”

Clinical Observation and Prognostic Analysis of Patients With Klebsiella pneumoniae Bloodstream Infection

“…XDR-KP is resistant to many antibiotics currently used in the clinic, except for tigecycline and polymyxin. But, emergence of high level of resistance against latest generation of tigecycline in animals and humans is concerning (He et al, 2019;Gasparrini et al, 2020). BSI caused by strain often aggravates the disease, resulting in difficult treatment and poor clinical prognosis.…”

“…Previous studies have discussed BSIs caused by K. Pneumoniae (Daikos et al, 2014;Gomez-Simmonds et al, 2016;Tsala et al, 2019;Gasparrini et al, 2020;Lee et al, 2020). However, the risk factors for drug-resistant bacterial infection and death of patients with bacteremia are still inconsistent among the different studies; thus, these risk factors still need to be further improved and verified in clinical practice (Du et al, 2002;Ben-David et al, 2012;Giannella et al, 2019;Lee et al, 2019).…”

Rapid Detection of High-Level Tigecycline Resistance in Tet(X)-Producing Escherichia coli and Acinetobacter spp. Based on MALDI-TOF MS

“…The Tet(X) proteins are flavin monooxygenases that catalyze the degradation of tetracyclines and derivatives (Park et al, 2017 ). There are currently five that have been discovered in different bacterial species, Tet (X3), (X4), (X5), (X6), and (X7), and all confer high-level resistance to all tetracyclines including tigecycline and the newly Food and Drug Administration (FDA)-approved omadacycline and eravacycline; Tet (X), (X1), and (X2) mediate only first-generation and second-generation tetracycline resistance (He et al, 2019 ; Sun et al, 2019 ; Wang et al, 2019 ; Gasparrini et al, 2020 ). This poses a great threat to the clinical efficacy of the whole family of tetracycline antibiotics (Fang et al, 2020 ).…”