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At least 19 recordsLinked to original sources

PubMed1990

Transport of divalent cations with tetracycline as mediated by the transposon Tn10-encoded tetracycline resistance protein.

Tetracycline uptake into inverted membrane vesicles from Tn10-bearing Escherichia coli cells required divalent cations. The degree of the stimulation of tetracycline uptake by various divalent cations showed the following decreasing order: Co2+ greater than Mn2+ greater than Mg2+ greater than Cd2+ greater than Ca2+. This order is consistent with the increasing order of the dissociation constants for metal chelate complexes of tetracycline. The Hill constants for the tetracycline uptake rate with various divalent cation concentrations were one. These observations strongly suggested that a 1:1 complex of tetracycline and a divalent cation was transported by a tetracycline resistance protein. This notion was confirmed by our observations that 60Co2+ was actively taken up with tetracycline by the membrane vesicles prepared from resistant cells. In the absence of tetracycline, no uptake of 60Co2+ was observed. It is clear that the 60Co2+ uptake was mediated by the tetracycline resistance protein, because the membrane vesicles from tetracycline-sensitive cells did not show the uptake of 60Co2+ and tetracycline. The 60Co2+ uptake was inhibited in the presence of other divalent cations, without any significant effect on tetracycline uptake, indicating that these cations are also transported with tetracycline by the tetracycline resistance protein.

Biological Transport↗

PubMed1990

A tetracycline efflux gene on Bacteroides transposon Tn4400 does not contribute to tetracycline resistance.

Previously, we demonstrated that the Bacteroides transposon Tn4351, which confers tetracycline resistance only on aerobically grown Escherichia coli, carries a gene that codes for a tetracycline-inactivating enzyme (B. S. Speer and A. A. Salyers, J. Bacteriol. 170:1423-1429, 1988). However, Park et al. (B. H. Park, M. Hendricks, M. H. Malamy, F. P. Tally, and S. B. Levy, Antimicrob. Agents Chemother. 31:1739-1743, 1987) showed that E. coli carrying a closely related transposon, Tn4400, exhibits energy-dependent efflux of tetracycline as well as tetracycline-inactivating activity (B. H. Park and S. B. Levy, Antimicrob. Agents Chemother. 32:1797-1800, 1988). This result raised the question of whether efflux or inactivation or a combination of the two was necessary for resistance conferred by both transposons. We showed that cells carrying Tn4351 did not exhibit the clear-cut efflux activity seen with cells carrying Tn4400 but rather exhibited a tetracycline accumulation profile which could be explained solely on the basis of inactivation of tetracycline in the cytoplasm and rapid diffusion of altered tetracycline out of the cell. Additionally, we were able to clone the efflux and tetracycline-modifying genes of Tn4400 separately. The region carrying the efflux gene spanned one of the two regions in which Tn4400 differs from Tn4351. A clone containing the corresponding region of Tn4351 did not exhibit efflux. Thus, it appears that Tn4351 does not have the efflux gene and that efflux makes no contribution to the resistance conferred by Tn4351. The MIC for cells carrying the subclone from Tn4400 that contained only the gene for tetracycline inactivation was the same that for cells carrying both the inactivation and efflux genes. Cells carrying only the gene for tetracycline efflux were tetracycline sensitive. This was true even when the efflux gene was on a high-copy-number plasmid which increased the level of efflux to that associated with the Tcr gene on pBR328. These results indicate that efflux activity does not contribute significantly to the tetracycline resistance conferred by Tn4400.

Bacteroides↗

PubMed1992

Tissue concentration and localization of tetracycline following site-specific tetracycline fiber therapy.

The primary objective of this study was to evaluate the concentration and location of tetracycline hydrochloride in tissue adjacent to periodontal pockets treated with a tetracycline impregnated fiber. A secondary objective was to determine if the presurgical placement of fibers had any adverse effects on healing following periodontal surgery. The study population consisted of 10 patients with at least 2 pockets in both maxillary quadrants of > or = 5 mm in depth and exhibiting bleeding on probing. After an initial scaling and root planing, placebo or tetracycline fibers were randomly assigned by quadrant to 2 non-adjacent pockets. Fibers were removed at the time of surgery; i.e., day 8, and periodontal surgery was performed utilizing a flap incision that allowed biopsy of 1 interdental papilla from each of the 2 test sites in each quadrant. One biopsy was analyzed for tetracycline concentrations by high performance liquid chromatography (HPLC). The second biopsy was examined by both light and ultraviolet fluorescence microscopy to determine the location of residual tetracycline and the intensity of inflammatory cell infiltrates. Results showed that the tissue concentration of the antibiotic in tetracycline treated sites was 64.4 +/- 7.01 ng/mg (ng of tetracycline/mg tissue weight) which corresponds to 43 micrograms of tetracycline and was below levels of accurate measurement in placebo treated sites. Tetracycline tissue concentrations corresponded to the ultraviolet fluorescence microscopy with a Pearson correlation coefficient of r = 0.92. Tetracycline fluorescence was noted in the soft tissue wall ranging from 1 to 20 microns.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2025

C10-Benzoate Esters of Anhydrotetracycline Inhibit Tetracycline Destructases and Recover Tetracycline Antibacterial Activity.

Tetracyclines (TCs) are an important class of antibiotics threatened by enzymatic inactivation. These tetracycline-inactivating enzymes, also known as tetracycline destructases (TDases), are a subfamily of class A flavin monooxygenases (FMOs) that catalyze hydroxyl group transfer and oxygen insertion (Baeyer-Villiger type) reactions on TC substrate scaffolds. Semisynthetic modification of TCs (e.g., tigecycline, omadacycline, eravacycline, and sarecycline) has proven effective in evading certain resistance mechanisms, such as ribosomal protection and efflux, but does not protect against TDase-mediated resistance. Here, we report the design, synthesis, and evaluation of a new series of 22 semisynthetic TDase inhibitors that explore D-ring substitution of anhydrotetracycline (aTC) including 14 C10-benzoate ester and eight C9-benzamides. Overall, the C10-benzoate esters displayed enhanced bioactivity and water solubility compared to the corresponding C9-benzamides featuring the same heterocyclic aryl side chains. The C10-benzoate ester derivatives of aTC were prepared in a high-yield one-step synthesis without the need for protecting groups. The C10-esters are water-soluble, stable toward hydrolysis, and display dose-dependent rescue of tetracycline antibiotic activity in E. coli expressing two types of tetracycline destructases, represented by TetX7 (Type 1) and Tet50 (Type 2). The best inhibitors recovered tetracycline antibiotic activity at concentrations as low as 2 μM, producing synergistic scores <0.5 in the fractional inhibitory concentration index (FICI) against TDase-expressing strains of E. coli and clinical P. aeruginosa. The C10-benzoate ester derivatives of aTC reported here are promising new leads for the development of tetracycline drug combination therapies to overcome TDase-mediated antibiotic resistance.

Anti-Bacterial Agents↗

PubMedDate not supplied

A placebo-controlled study to evaluate the efficacy of topical tetracycline and oral tetracycline in the treatment of mild to moderate acne. Dermatology Research Group.

This double-blind, parallel group multicentre study in 85 hospital out-patients with mild to moderate acne evaluated the efficacy of 2.2 mg/ml topical tetracycline or placebo applied twice daily for 16 weeks together with an initial course of oral tetracycline, at doses of 1000 mg/day during weeks 1-4 and 500 mg/day during weeks 5-8. Acne severity improved significantly (P less than 0.01) with both treatments after 8 and 16 weeks. After 4 weeks, 78% of patients using topical tetracycline showed reduced acne severity compared with 50% using placebo and, by week 16, improvements were 94% and 57%, respectively (P = 0.035). Global evaluations of patients and of investigators showed most improvement to occur within the first 8 weeks of treatment. Tingling and stinging were the most frequently reported adverse effects, occurring in similar frequencies in both treatment groups. Skin discoloration was more frequent in patients given topical tetracycline. Overall, 90% of patients rated topical tetracycline as 'cosmetically acceptable'. In conclusion, topical tetracycline is useful in treatment of mild to moderate acne when given with an initial course of oral tetracycline and may enhance efficacy without unacceptable side-effects.

Acne Vulgaris↗

PubMed1990

Metal-tetracycline/H+ antiporter of Escherichia coli encoded by a transposon, Tn10. The role of the conserved dipeptide, Ser65-Asp66, in tetracycline transport.

The transposon Tn10-encoded tetracycline resistance protein functions as a metal-tetracycline/H+ antiporter (Yamaguchi, A., Udagawa, T., and Sawai, T. (1990) J. Biol. Chem. 265, 4809-4813). The Ser65-Asp66 dipeptide is conserved in all known tetracycline antiporter proteins and is an important target for site-directed mutagenesis. When Asp66 was replaced by Asn, the transport activity was completely lost, whereas when it was replaced by Glu, the activity was reduced to 10% of the wild-type level, indicating that a negative charge at position 66 is essential for tetracycline transport. Replacement of Ser65 by Cys or Ala, in contrast, caused only a minor change in tetracycline transport activity. However, the Cys65 mutant antiporter was sensitive to sulfhydryl reagents. Complete inactivation of the Cys65 antiporter by N-ethylmaleimide was not prevented by the substrate. A less bulky reagent, methyl methanethiosulfonate, caused partial inactivation of the Cys65 antiporter without changing its affinity to the substrate. These results indicate that a region including the dipeptide plays an important role in metal-tetracycline transport except for substrate binding. It may act as a gate which opens on the charge-charge interaction between Asp66 and the metal-tetracycline.

Amino Acid Sequence↗

PubMed1975

Effectiveness of achievable urinary concentrations of tetracyclines against "tetracycline-resistant" pathogenic bacteria.

Hospitalized patients with urinary tract infections caused by Pseudomonas aeruginosa or other bacterial pathogens are frequently treated with parenteral antibiotics such as gentamicin. Many of these organisms are shown by Kirby-Bauer disk sensitivity testing to be resistant to tetracycline. One hundred seventy-one such tetracycline-resistant bacterial isolates were studied; 84% were found to be sensitive to achievable urinary concentrations of tetracycline. Two patients with long-standing chronic urinary tract infection with Pseudomonas were treated with tetracycline for a year and a half with excellent results. In a pilot clinical trial, eight of 12 hospitalized patients with urinary tract infection were treated successfully with tetracycline without regard to disk sensitivity data. Institution of tetracycline as soon as the microscopic diagnosis of urinary tract infection is made might be an acceptable empiric approach to the treatment of urinary infection in hospitalized patients who do not show evidence of sepsis.

Bacteriuria↗

PubMed1977

Penetration of ocular compartments by tetracyclines. I. An experimental study with tetracycline.

Total antibiotic concentration of tetracycline hydrochloride was determined in the ocular structures of rabbits by radioactive tracer method. Concentration of tetracycline of 0.1 to 5 microgram/g, adequate to inhibit the growth of bacteria of high or medium susceptibility, was measured from all ocular structures with the exception of the lens. Tetracycline concentration in the aqueous humor was inferior to that in the vascularized ocular tissues and to that in the cornea. Vitreous body tetracycline level, about 0.3 microgram/g, was about half of the concentration in the aqueous humor. The disruption of the blood-aqueous barrier following paracentesis led to an immediate increase of tetracycline concentration in the anterior structures of the eye.

Animals↗

PubMed1976

Topical use of tetracycline in the treatment of acne: a double-blind study comparing topical and oral tetracycline therapy and placebo.

A group of 75 subjects with moderate or severe acne was divided by random selection into three treatment groups. One group was treated with a topically applied placebo liquid and with 500 mg of orally administered tetracycline hydrochloride daily; one group received orally administered lactose capsules and topically applied placebo liquid each day; and one group was treated with orally administered lactose capsules and with a topical preparation containing tetracycline hydrochloride and n-decylmethyl sulfoxide, an agent intended to enhance antibiotic penetration. At the conclusion of the 13-week study and at several points during the study, the conditions of the subjects receiving topically or orally administered tetracycline hydrochloride were significantly (P less than .05) more improved than the conditions of the subjects receiving lactose capsules and the topically applied placebo liquid. However, there was no significant difference between the effects of topically and orally administered tetracycline hydrochloride.

Acne Vulgaris↗

PubMed1979

Differential pulse polarography of tetracycline: determination of complexing tendencies of tetracycline analogs in the presence of cations.

The complexation tendencies, stoichiometries, and stability constants for tetracycline, minocycline, and demeclocycline with the metallic ions calcium(II), magnesium (II), zinc(II), aluminum(III), iron(II), and iron (III) were evaluated using a polarographic technique. Changes in pulse peak heights for each tetracycline deravative were measured as a function of cation concentration. The method provides an in vitro method of evaluating the selectivity of particular metal ions for different tetracycline analogs.

Aluminum↗

PubMed1991

Stoichiometry of metal-tetracycline/H+ antiport mediated by transposon Tn10-encoded tetracycline resistance protein in Escherichia coli.

The tetracycline resistance protein (TetA) endoded by transposon Tn10 mediates the efflux of divalent cation-tetracycline chelating complexes [Yamaguchi, A., Udagawa, T. and Sawai, T. (1990) J. Biol. Chem. 265, 4809-4813]. It was confirmed that protons were antiported with the complexes through an electrically-neutral process because the antiport consumed delta pH but not delta psi. The quantitative relationship between delta pH and delta pTC determined by a flow-dialysis method clearly indicated a 1:1 stoichiometry of the monocationic metal-tetracycline/H+ exchange.

Cell-Free System↗

PubMed1991

Structural requirements of tetracycline-Tet repressor interaction: determination of equilibrium binding constants for tetracycline analogs with the Tet repressor.

We used the Tn10-encoded Tet repressor, which has a highly specific binding capacity for tetracycline, to probe contacts between the drug and protein by chemical interference studies of the antibiotic. For that purpose, the equilibrium association constants of modified tetracyclines with the Tet repressor and Mg2+ cations were determined quantitatively. The results confirm the previous notion that Mg2+ probably binds with the oxygens at positions 11 and 12 and is absolutely required for protein-drug recognition. Modifications were introduced at positions seven, six, five, and four of the drug, and anhydrotetracycline was also studied. Substitutions or eliminations of functions at these positions influenced binding to the Tet repressor up to 35-fold. The introduction of an azido function at position seven in 7-azidotetracycline and epimerization of the substituents at position four in 4-epitetracycline lead to a 2- or 25-fold reduction, respectively, of Tet repressor affinity in those compounds. Anhydrotetracycline bound about 35-fold more strongly than tetracycline did, indicating that the oxygen at position 11 may be involved in Tet repressor recognition. This increased binding is in contrast to the lower antibiotic activity of anhydrotetracycline and indicates that the Tet repressor and ribosomes recognize the drug differently.

Bacterial Proteins↗

PubMed1976

R factor-mediated tetracycline resistance in Escherichia coli K12. Dominance of some tetracycline sensitive mutants and relief of dominance by deletion.

Strains of Escherichia coli K12 heterozygous for the R100-1 tetracycline resistance region were constructed. They carried the wild-type Tetr genes in the chromosome and single site Tets mutations on plasmids. Some heterozygotes could not express tetracycline resistance fully after induction. The mutant tet allele was thus partially dominant. When heterozygotes carrying the dominant tet mutant were plated on agar containing 20 mg/ml tetracycline, mutants which grew normally occurred at a frequency of 1-4 X 10(-4). Analysis of these dominance relief mutants showed that in 53/56 isolates the dominant tet allele was lost forming either Tra+ or Tra- deletion mutants of the plasmid. The mutation frequency was not affected either by the host chromosomal recA mutation or by the temperature of growth of the culture.

Chromosome Deletion↗

PubMed1992

Tet determinants provide poor protection against some tetracyclines: further evidence for division of tetracyclines into two classes.

Atypical tetracyclines were active against Escherichia coli and Staphylococcus aureus strains containing determinants that mediate resistance to typical tetracyclines by efflux (Tet B and Tet K) or ribosomal protection (Tet M) mechanisms. The results support recently published data that tetracyclines are divisible into at least two classes on the basis of their modes of action.

Escherichia coli↗

PubMed1977

[Comparative study of the physicochemical properties of the surface of Escherichia, their sensitivity to ampicillin and tetracycline and their capacity to absorb tetracycline].

Development of resistance to ampicillin and tetracycline in Escherichia resulted in an increase in the electrokinetic potential and a decrease in the level of hydration and isoelectric values of pH. The changes in the hydration level mainly depended on the accompanying dissociation. Studies on 3H-tetracycline binding revealed a low accumulation capacity of the resistant mutants. The rate of 3H-tetracycline binding did not depend on the changes in the physico-chemical parameters of the cell surface due to resistance and dissociation.

Absorption↗

PubMed1977

[Effect of tetracycline base crystallization on the conditions properties of the powders and drug forms obtained. The development of directed crystallization procedures for tetracycline base].

The study of the process of tetracycline base crystallization showed that with an increase in the rate of pH, temperature and mixed rotation changes, the specific surface of the crystalline precipitate increased with a simultaneous decrease in the bulk weight, looseness and volume density of the powder. The residual content of tetracycline in the mother solution decreased. The level of the effect of various parameters on the final results was different.

Chemistry, Pharmaceutical↗

PubMed1979

Distribution of pyrrolidinomethyl-tetracycline (rolitetracycline) and tetracycline in blood and various organs of mice measured by high pressure liquid chromatography.

By means of a newly developed high-pressure liquid chromatographic method the organ distribution of tetracycline (TC) and pyrrolidinomethyl-tetracycline (PMT) has been studied. When mice were treated with 50 mg/kg i.v. TC or PMT these antibiotics could be detected in all organs investigated (liver, kidney, heart, lung, muscle, spleen). Especially high concentrations were found in liver and kidneys, where TC and PMT could be detected up to 6 h. In animals treated with PMT part of the PMT applied decomposed slowly yielding TC, which was found together with PMT in blood and all organs.

Animals↗

PubMed1977

New compounds: organoboron derivatives of tetracyclines I: synthesis of carboxamido derivative of tetracycline with perhydro-2-phenyl-1,3,6,2-dioxazaborocine.

An organoboron carboxamido derivative of tetracycline, designed for use in the 105B-thermal neutron-capture treatment of cancer, was synthesized under the conditions of the Mannich reaction using perhydro-2-phenyl-1,3,6,2-dioxazaborocine as the amine component. Spectral data (UV, IR, and NMR) for the compound and its hydrolytic stability are discussed.

Boron Compounds↗