ArticleBMC biology2021
Structural and mechanistic basis of the high catalytic activity of monooxygenase Tet(X4) on tigecycline.
Article in BMC biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 15 citations in OpenAlex.
- Evolution, Mechanisms, and Therapeutic Implications of Mobile Tetracycline Destructases.BioEssays : news and reviews in molecular, cellular and developmental biology · 2026Review
- Evidence that SmTetX is not a tetracycline resistance determinant.Microbiology spectrum · 2026Article
- Targeting Bacterial Infections in Periodontal Disease: From Conventional Antibiotics to Next-Generation Therapeutics.Antibiotics (Basel, Switzerland) · 2026Review
- Genome-guided discovery and computational prioritization of next generation drug development fromFrontiers in microbiology · 2026Article
- Covalent Irreversible Inhibitors of Tetracycline Destructases.ACS infectious diseases · 2025Article
- Binding assays enable discovery of Tet(X) inhibitors that combat tetracycline destructase resistance.Chemical science · 2025Article
- Genomic Insights into Colistin and Tigecycline Resistance in ESBL-ProducingAntibiotics (Basel, Switzerland) · 2025Article
- Based on quorum sensing: reverse effect of traditional Chinese medicine on bacterial drug resistance mechanism.Frontiers in cellular and infection microbiology · 2025Review
- Potential Convergence to Accommodate Pathogenicity Determinants and Antibiotic Resistance Revealed inMicroorganisms · 2024Article
- Synergistic Role of Biofilm-Associated Genes and Efflux Pump Genes in Tigecycline Resistance of Acinetobacter baumannii.Medical science monitor : international medical journal of experimental and clinical research · 2023Article
- Tetracycline-modifying enzyme SmTetX from Stenotrophomonas maltophilia.Acta crystallographica. Section F, Structural biology communications · 2023Article
- Structure of anhydrotetracycline-bound Tet(X6) reveals the mechanism for inhibition of type 1 tetracycline destructases.Communications biology · 2023Article
- Structure-Based Design of Bisubstrate Tetracycline Destructase Inhibitors That Block Flavin Redox Cycling.Journal of medicinal chemistry · 2023Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTigecycline is a tetracycline derivative that constitutes one of the last-resort antibiotics used clinically to treat infections caused by both multiple drug-resistant (MDR) Gram-negative and Gram-positive bacteria. Resistance to this drug is often caused by chromosome-encoding mechanisms including over-expression of efflux pumps and ribosome protection. However, a number of variants of the flavin adenine dinucleotide (FAD)-dependent monooxygenase TetX, such as Tet(X4), emerged in recent years as conferring resistance to tigecycline in strains of Enterobacteriaceae, Acinetobacter sp., Pseudomonas sp., and Empedobacter sp. To date, mechanistic details underlying the improvement of catalytic activities of new TetX enzymes are not available.
resultsIn this study, we found that Tet(X4) exhibited higher affinity and catalytic efficiency toward tigecycline when compared to Tet(X2), resulting in the expression of phenotypic tigecycline resistance in E. coli strains bearing the tet(X4) gene. Comparison between the structures of Tet(X4) and Tet(X4)-tigecycline complex and those of Tet(X2) showed that they shared an identical FAD-binding site and that the FAD and tigecycline adopted similar conformation in the catalytic pocket. Although the amino acid changes in Tet(X4) are not pivotal residues for FAD binding and substrate recognition, such substitutions caused the refolding of several alpha helixes and beta sheets in the secondary structure of the substrate-binding domain of Tet(X4), resulting in the formation of a larger number of loops in the structure. These changes in turn render the substrate-binding domain of Tet(X4) more flexible and efficient in capturing substrate molecules, thereby improving catalytic efficiency.
conclusionsOur works provide a better understanding of the molecular recognition of tigecycline by the TetX enzymes; these findings can help guide the rational design of the next-generation tetracycline antibiotics that can resist inactivation of the TetX variants.
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