The chemistry and cellular biology of the tetracyclines

Nelson, Mark L.

doi:10.1007/978-3-0348-8306-1_1

Cited by 18 publications

(20 citation statements)

References 92 publications

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“…The omadacycline C4-epimer (inversion of stereochemistry at carbon-4), which is pharmacologically inactive, was the only prominent additional chromatographic peak seen and was also present in the dose solution. Reversible epimerization at the 4-position is a well-known phenomenon for members of this antibiotic class and has been attributed to a variety of factors, such as pH, solvent and temperature (Nelson, 2001). The absence of metabolites with omadacycline is in contrast to the major in vivo biotransformation reactions in humans for tigecycline, a structurally similar glycylcycline antibiotic, where both amide hydrolysis of the glycinecontaining side chain and glucuronidation of the phenol nearest the side chain occur in vitro and in vivo (Hoffmann et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Clinical disposition, metabolism and in vitro drug–drug interaction properties of omadacycline

Flarakos

et al. 2016

Xenobiotica

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(2017) Clinical disposition, metabolism and invitro drug-drug interaction properties of omadacycline, Xenobiotica, 47:8, 682-696, DOI: 10.1080/00498254.2016 Omadacycline was a substrate of P-glycoprotein, but not of the other transporters. 3. Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300 mg oral dose of [ 14 C]-omadacycline (36.6 mCi). Absorption was rapid with peak radioactivity ($610 ngEq/mL) between 1-4 h in plasma or blood. The AUC last of plasma radioactivity (only quantifiable to 8 h due to low radioactivity) was 3096 ngEq h/mL and apparent terminal half-life was 11.1 h. Unchanged omadacycline reached peak plasma concentrations ($563 ng/mL) between 1-4 h. Apparent plasma half-life was 17.6 h with biphasic elimination. Plasma exposure (AUC inf ) averaged 9418 ng h/mL, with high clearance (CL/F, 32.8 L/h) and volume of distribution (Vz/F 828 L). No plasma metabolites were observed. 4. Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.

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Section: Discussionmentioning

confidence: 99%

“…The chemical and radiochemical purity was !90% (with no unspecified impurity >1.0%) as verified by high-pressure liquid chromatography (HPLC). The major impurity was the omadacycline C4-epimer (a common impurity for this class of molecule (Nelson, 2001), with several trace impurities as described later.…”

Section: Human Mass Balance and Dispositionmentioning

confidence: 97%

Clinical disposition, metabolism and in vitro drug–drug interaction properties of omadacycline

Flarakos

et al. 2016

Xenobiotica

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“…Tetracyclines bind to bacterial ribosomes, interfering with the association of aminoacyl-tRNAs with ribosomes (13,43). Due to their efficacy against both gram-positive and gram-negative bacteria and low toxicity for eukaryotic cells, tetracycline is used in a long list of human clinical and nonclinical applications for controlling bacterial growth (13).…”

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confidence: 99%

Isolation of Tetracycline-Resistant Megasphaera elsdenii Strains with Novel Mosaic Gene Combinations of tet (O) and tet (W) from Swine

Stanton

Humphrey

2003

Appl Environ Microbiol

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Anaerobic bacteria insensitive to chlortetracycline (64 to 256 g/ml) were isolated from cecal contents and cecal tissues of swine fed or not fed chlortetracycline. A nutritionally complex, rumen fluid-based medium was used for culturing the bacteria. Eight of 84 isolates from seven different animals were identified as Megasphaera elsdenii strains based on their large-coccus morphology, rapid growth on lactate, and 16S ribosomal DNA sequence similarities with M. elsdenii LC-1 T . All eight strains had tetracycline MICs of between 128 and 256 g/ml. Based on PCR assays differentiating 14 tet classes, the strains gave a positive reaction for the tet(O) gene. By contrast, three ruminant M. elsdenii strains recovered from 30-year-old culture stocks had tetracycline MICs of 4 g/ml and did not contain tet genes. The tet genes of two tetracycline-resistant M. elsdenii strains were amplified and cloned. Both genes bestowed tetracycline resistance (MIC ‫؍‬ 32 to 64 g/ml) on recombinant Escherichia coli strains. Sequence analysis revealed that the M. elsdenii genes represent two different mosaic genes formed by interclass (double-crossover) recombination events involving tet(O) and tet(W). One or the other genotype was present in each of the eight tetracycline-resistant M. elsdenii strains isolated in these studies. These findings suggest a role for commensal bacteria not only in the preservation and dissemination of antibiotic resistance in the intestinal tract but also in the evolution of resistance.

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“…Moreover, they report that this biosensor predominantly responds to zwitterionic tetracycline, which highlight the role of pH in the biological activity of this antibiotic. Tetracycline complexation by calcium changes the neutral keto-tautomer required for membrane crossing to a charged enol form essential for ribosomal docking (Nelson, 2001;Zakeri and Wright, 2008).…”

Section: Effect Of Feed Crude Protein and Calcium Content On The Bioamentioning

confidence: 98%

“…This phenomenon, as well as tetracycline complexation by divalent cations (Chopra and Roberts, 2001), is susceptible to charge number and type of charges (Nelson, 2001). In relation to this, Zhang et al (2014) showed recently that tetracycline uptake by E. coli MT102-PIR/pUTtetgfp decreases ca.…”

Section: Effect Of Feed Crude Protein and Calcium Content On The Bioamentioning

confidence: 98%

Bioavailability of in-feed tetracyclines is influenced to a greater extent by crude protein rather than calcium

Granados-Chinchilla¹,

Rodríguez²

2014

Animal Feed Science and Technology

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The chemistry and cellular biology of the tetracyclines

Cited by 18 publications

References 92 publications

Clinical disposition, metabolism and in vitro drug–drug interaction properties of omadacycline

Clinical disposition, metabolism and in vitro drug–drug interaction properties of omadacycline

Isolation of Tetracycline-Resistant Megasphaera elsdenii Strains with Novel Mosaic Gene Combinations of tet (O) and tet (W) from Swine

Bioavailability of in-feed tetracyclines is influenced to a greater extent by crude protein rather than calcium

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