Bismuth Drugs Reverse Tet(X)-Conferred Tigecycline Resistance in Gram-Negative Bacteria

Deng, Tian; Jia, Yuqian; Tong, Ziwen; Shi, Jingru; Wang, Zhiqiang; Lv, Yuan

doi:10.1128/spectrum.01578-21

Cited by 14 publications

(17 citation statements)

References 36 publications

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“…Since the report of tet (X3/4), the degradative enzyme mechanism has gained more and more attention ( He et al, 2019 ; Xu et al, 2022 ). At present, bismuth drugs and plumbagin can be used as Tet(X) inhibitors to improve the sensitivity of strains to tigecycline, which provides a new therapeutic strategy for the treatment of tigecycline-resistant bacterial infections ( Deng et al, 2022 ; Xu et al, 2022 ).…”

Section: Mechanism Of Tigecycline Resistancementioning

confidence: 99%

Dissemination and prevalence of plasmid-mediated high-level tigecycline resistance gene tet (X4)

Zhang

Wen²,

Wang³

et al. 2022

Front. Microbiol.

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With the large-scale use of antibiotics, antibiotic resistant bacteria (ARB) continue to rise, and antibiotic resistance genes (ARGs) are regarded as emerging environmental pollutants. The new tetracycline-class antibiotic, tigecycline is the last resort for treating multidrug-resistant (MDR) bacteria. Plasmid-mediated horizontal transfer enables the sharing of genetic information among different bacteria. The tigecycline resistance gene tet(X) threatens the efficacy of tigecycline, and the adjacent ISCR2 or IS26 are often detected upstream and downstream of the tet(X) gene, which may play a crucial driving role in the transmission of the tet(X) gene. Since the first discovery of the plasmid-mediated high-level tigecycline resistance gene tet(X4) in China in 2019, the tet(X) genes, especially tet(X4), have been reported within various reservoirs worldwide, such as ducks, geese, migratory birds, chickens, pigs, cattle, aquatic animals, agricultural field, meat, and humans. Further, our current researches also mentioned viruses as novel environmental reservoirs of antibiotic resistance, which will probably become a focus of studying the transmission of ARGs. Overall, this article mainly aims to discuss the current status of plasmid-mediated transmission of different tet(X) genes, in particular tet(X4), as environmental pollutants, which will risk to public health for the “One Health” concept.

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Section: Mechanism Of Tigecycline Resistancementioning

confidence: 99%

Dissemination and prevalence of plasmid-mediated high-level tigecycline resistance gene tet (X4)

Zhang

Wen²,

Wang³

et al. 2022

Front. Microbiol.

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“…Multiple recent studies have suggested combination therapy consisting of a tetracycline antibiotic with a TDase inhibitor is also feasible 12 , 33 – 35 . Park et al reported that anhydrotetracycline can rescue tetracycline efficacy in pathogens expressing Tet(56), a type 2 TDase 12 .…”

Section: Discussionmentioning

confidence: 99%

“…Xu et al established that plumbagin, a natural naphthoquinone isolated from plants, shows synergistic effects with tetracycline antibiotics against Tet(X3)-/Tet(X4)-producing bacteria 34 . Deng et al confirmed a combination of Bi(NO 3 ) 3 and tigecycline can prevent development of resistance in bacteria expressing Tet(X) 35 . Most recently, Williford et al reported a series of C9-benzamide and C9-benzylamine anhydrotetracycline analogs that act as bisubstrate inhibitors of type 1 and type 2 TDases 32 .…”

Section: Discussionmentioning

confidence: 99%

Structure of anhydrotetracycline-bound Tet(X6) reveals the mechanism for inhibition of type 1 tetracycline destructases

Kumar

Williford

Blake³

et al. 2023

Commun Biol

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Inactivation of tetracycline antibiotics by tetracycline destructases (TDases) remains a clinical and agricultural threat. TDases can be classified as type 1 Tet(X)-like TDases and type 2 soil-derived TDases. Type 1 TDases are widely identified in clinical pathogens. A combination therapy of tetracycline and a TDase inhibitor is much needed to rescue the clinical efficacy of tetracyclines. Anhydrotetracycline is a pan-TDase inhibitor that inhibits both type 1 and type 2 TDases. Here, we present structural, biochemical, and phenotypic evidence that anhydrotetracycline binds in a substrate-like orientation and competitively inhibits the type 1 TDase Tet(X6) to rescue tetracycline antibiotic activity as a sacrificial substrate. Anhydrotetracycline interacting residues of Tet(X6) are conserved within type 1 TDases, indicating a conserved binding mode and mechanism of inhibition. This mode of binding and inhibition is distinct from anhydrotetracycline’s inhibition of type 2 TDases. This study forms the framework for development of next-generation therapies to counteract enzymatic tetracycline resistance.

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“…The same trend was true, although less pronounced, for compound 14 against Tet(X7) (Figure S15). These A variety of TDase inhibitors have been reported, including AZT, 43 bismuth salts, 44 flavonoids, 45 and aTC. 16 The development of selective inhibitors for enzymes in the FMO superfamily has been challenging due in part to the mechanistic complexity, dynamic nature, and substrate flexibility observed for this enzyme class.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Structure-Based Design of Bisubstrate Tetracycline Destructase Inhibitors That Block Flavin Redox Cycling

Williford

DeAngelo

Blake³

et al. 2023

J. Med. Chem.

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Tetracyclines (TCs) are an important class of antibiotics threatened by an emerging new resistance mechanismenzymatic inactivation. These TC-inactivating enzymes, also known as tetracycline destructases (TDases), inactivate all known TC antibiotics, including drugs of last resort. Combination therapies consisting of a TDase inhibitor and a TC antibiotic represent an attractive strategy for overcoming this type of antibiotic resistance. Here, we report the structure-based design, synthesis, and evaluation of bifunctional TDase inhibitors derived from anhydrotetracycline (aTC). By appending a nicotinamide isostere to the C9 position of the aTC D-ring, we generated bisubstrate TDase inhibitors. The bisubstrate inhibitors have extended interactions with TDases by spanning both the TC and presumed NADPH binding pockets. This simultaneously blocks TC binding and the reduction of FAD by NADPH while “locking” TDases in an unproductive FAD “out” conformation.

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Bismuth Drugs Reverse Tet(X)-Conferred Tigecycline Resistance in Gram-Negative Bacteria

Cited by 14 publications

References 36 publications

Dissemination and prevalence of plasmid-mediated high-level tigecycline resistance gene tet (X4)

Dissemination and prevalence of plasmid-mediated high-level tigecycline resistance gene tet (X4)

Structure of anhydrotetracycline-bound Tet(X6) reveals the mechanism for inhibition of type 1 tetracycline destructases

Structure-Based Design of Bisubstrate Tetracycline Destructase Inhibitors That Block Flavin Redox Cycling

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