ArticlemSystems2021
Evolutionary Trajectory of the Tet(X) Family: Critical Residue Changes towards High-Level Tigecycline Resistance.
Article in mSystems, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- Evolution, Mechanisms, and Therapeutic Implications of Mobile Tetracycline Destructases.BioEssays : news and reviews in molecular, cellular and developmental biology · 2026Review
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- Threat and Control ofFoods (Basel, Switzerland) · 2025Review
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- Genomic Diversity of theMicroorganisms · 2025Article
- Emergence of transferable tigecycline and eravacycline resistance gene tet(X4) in Escherichia coli isolates from Iran.Scientific reports · 2025Article
- AdeABC, AdeFGH, and AdeIJK efflux pumps as key factors in tigecycline resistance of Acinetobacter baumannii: a study from Western Balkan hospitals.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2025Article
- Epidemiology and resistance mechanisms of tigecycline- and carbapenem-resistantFrontiers in microbiology · 2025Article
- Evolution, dissemination, and genetic dynamics of the carbapenem resistance geneFrontiers in cellular and infection microbiology · 2025Article
- Comparative Genomic Analysis of Tigecycline Resistance Development in ClinicalInfection and drug resistance · 2025Article
- Concurrence of Inactivation Enzyme-Encoding GenesFoods (Basel, Switzerland) · 2024Article
- Cinnamaldehyde targets SarA to enhance β-lactam antibiotic activity against methicillin-resistantmLife · 2024Article
- Genome-based assessment of antimicrobial resistance reveals the lineage specificity of resistance and resistance gene profiles inMicrobiology spectrum · 2024Article
- A rapid liquid chromatography-tandem mass spectrometry based method for the detection of Tet(X) resistance gene inFrontiers in microbiology · 2024Article
- Molecular mechanisms of tigecycline-resistance amongFrontiers in cellular and infection microbiology · 2024Review
- Identification of novel Tet(X6)-Tet(X2) recombinant variant inFrontiers in microbiology · 2024Article
- Review
- A promising metabolite, 9-aminominocycline, restores the sensitivity of tigecycline againstFrontiers in microbiology · 2024Article
- Resistance mechanisms of tigecycline inFrontiers in cellular and infection microbiology · 2023Review
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
Abstract
The emergence of the plasmid-mediated high-level tigecycline resistance mechanism Tet(X) threatens the role of tigecycline as the "last-resort" antibiotic in the treatment of infections caused by carbapenem-resistant Gram-negative bacteria. Compared with that of the prototypical Tet(X), the enzymatic activities of Tet(X3) and Tet(X4) were significantly enhanced, correlating with high-level tigecycline resistance, but the underlying mechanisms remain unclear. In this study, we probed the key amino acid changes leading to the enhancement of Tet(X) function and clarified the structural characteristics and evolutionary path of Tet(X) based upon the key residue changes. Through domain exchange and site-directed mutagenesis experiments, we successfully identified five candidate residues mutations (L282S, A339T, D340N, V350I, and K351E), involved in Tet(X2) activity enhancement. Importantly, these 5 residue changes were 100% conserved among all reported high-activity Tet(X) orthologs, Tet(X3) to Tet(X7), suggesting the important role of these residue changes in the molecular evolution of Tet(X). Structural analysis suggested that the mutant residues did not directly participate in the substrate and flavin adenine dinucleotide (FAD) recognition or binding, but indirectly altered the conformational dynamics of the enzyme through the interaction with adjacent residues. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and UV full-wavelength scanning experiments confirmed that each mutation led to an increase in activity without changing the biochemical properties of the Tet(X) enzyme. Further phylogenetic analysis suggested that
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