A Divergent Route to Eravacycline

Zhang, Wu‐Yan; Che, Qinglin; Crawford, Scott; Rönn, Magnus; Dunwoody, Nicholas

doi:10.1021/acs.joc.6b02442

Cited by 14 publications

(14 citation statements)

References 10 publications

(22 reference statements)

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“…Here, we demonstrate that Tet (X7) encodes the improved catalytic efficiency of the soil-derived enzyme Tet (50) and additionally has an expanded substrate scope for inactivation of third-generation tetracyclines. When enzymatic reactions using Tet(X) and Tet(X7) were analyzed by liquid chromatography-mass spectrometry, we observed the primary product of omadacycline, tigecycline, and (55) tet (47) tet (49) tet (52) tet (53) tet (48) tet (51) tet (50) tet (54) tet (56) Fig. 2 Phenotypic profiles of heterologously expressed tetracycline-inactivating enzymes correlate with habitat of origin.…”

Section: Resultsmentioning

confidence: 99%

“…In 2015, we substantially expanded the catalog of "tetracycline destructases" by identifying a family of tetracycline-inactivating enzymes, (Tet(47)-Tet(55)), from functional selections of environmental metagenomes 11 . Based on sequence homology to these soil-derived enzymes, we identified an additional enzyme, Tet (56), as a previously uncharacterized tetracycline resistance determinant in Legionella longbeachae. These enzymes are structurally and functionally homologous to Tet(X) 12 , the flavin-dependent monooxygenase (FMO) originally discovered in Bacteroides fragilis 13 .…”

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confidence: 99%

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

Gasparrini¹,

et al. 2020

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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.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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

Gasparrini¹,

et al. 2020

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“…[40][41][42] Te traphase Pharmaceuticals developed as ynthetic method for the preparation of 85 (Scheme 9). [42][43][44] Scheme5.Synthesis of intermediate 52. Figure 9) incorporates three heterocycles and one difluorinatedp henyl moiety.I tw as approved by the FDA in 2015 for the treatment of invasive aspergillosis and invasive mucormycosis.…”

Section: Ghsr1a Antagonistsmentioning

confidence: 99%

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Mei

Han

White

et al. 2020

Chemistry A European J

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Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor‐made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man‐made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

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“…Interestingly, the analysis of protein‐binding patterns of ERV ranged from 12.5% to −97.3% for an array of doses (2.5, 5, 6, 7.5, and 10 mg/kg), thus indicating that a fixed protein‐binding value for this antibiotic does not exist. Accounting for the protein‐binding profile and the measurement of free drug is crucial in the calculation of f AUC/MIC . In the future, more studies should be conducted to better explain the PK/PD parameters of ERV to advance its clinical utility.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Accounting for the protein-binding profile and the measurement of free drug is crucial in the calculation of fAUC/MIC. 27,29,30 In the future, more studies should be conducted to better explain the PK/PD parameters of ERV to advance its clinical utility.…”

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confidence: 99%

Evaluation of Eravacycline: A Novel Fluorocycline

et al. 2020

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Eravacycline (ERV), formerly known as TP‐434, is a novel tetracycline (TET) antibiotic that exhibits in vitro activity against various gram‐positive, gram‐negative aerobic and anaerobic pathogens, including those exhibiting TET‐specific acquired resistance mechanisms. Similar to other TETs, it inhibits protein synthesis through binding to the 30S ribosomal subunit. Eravacycline was approved by the United States Food and Drug Administration (FDA) in August 2018 for the treatment of complicated intraabdominal infections (cIAIs) in adults following the Investigating Gram‐Negative Infections Treated with Eravacycline (IGNITE)1 and IGNITE4 phase III trials. In these two, double‐blind, multicenter clinical trials, ERV was proven noninferior in terms of clinical response in comparison to ertapenem and meropenem, respectively. Eravacycline was well tolerated with nausea, vomiting, and infusion site reactions being the most commonly reported adverse reactions. Clinicians now have ERV as a novel therapeutic option for the treatment of adults with intraabdominal infections, allergies to β‐lactam agents, Clostridioides difficile‐associated diarrhea, or if tolerability to other agents is a concern.

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A Divergent Route to Eravacycline

Cited by 14 publications

References 10 publications

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

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

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Evaluation of Eravacycline: A Novel Fluorocycline

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