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PubMed1998

Screening of an inhibitor of the tetracycline efflux pump in a tetracycline-resistant clinical-isolate of Staphylococcus aureus 743.

Clinically-isolated methicillin-resistant Staphylococcus aureus (MRSA) strain 743 exhibited resistance to tetracycline as judged from the active efflux of the drug. The efflux of tetracycline was inhibited by an uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), and minocycline. Inhibitors of the efflux pump were examined in this strain to determine the cellular accumulation of tetracycline. Out of seven compounds examined, three caused a significant increase in the cellular concentration of tetracycline by inhibiting the efflux pump. Two of them seem to be energy inhibitors. Ro 07-3149 inhibited the efflux pump without affecting the energy state, and exhibited very low antibacterial activity but showed weak synergy with tetracycline.

Anti-Bacterial Agents↗
PubMed1999

Crystal structure of the tet repressor in complex with a novel tetracycline, 9-(N,N-dimethylglycylamido)- 6-demethyl-6-deoxy-tetracycline.

The tetracycline analog 9-(N, N-dimethylglycylamido)-6-demethyl-6-deoxy-tetracycline (9glyTc) belongs to a new group of tetracyclines called glycylcyclines. They are strong antibiotics showing reduced sensitivity against the major tetracycline resistance mechanisms. We have determined the crystal structure of 9glyTc in complex with Tet repressor class D, TetR(D), at 2.4 A resolution. Sterical hindrance at the entrance of the tetracycline binding tunnel of TetR by the bulky and charged glycyl amido substituent interferes with conformational changes required for the mechanism of induction, and leads to decreased induction efficiency as observed for point mutations of amino acid residues located in the neighbourhood to the glycylamido moiety of bound 9glyTc.

Crystallography, X-Ray↗
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↗
PubMed1980

Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in Escherichia coli.

Tetracycline resistance encoded by four genetically different determinants residing on plasmids in Escherichia coli was shown to be associated in each case with an energy-dependent decrease in accumulation of the antibiotic in whole cells in which resistance had been induced. The different class determinants examined were those on plasmids RP1 (class A), R222 (class B), R144 (class C), and RA1 (class D). This decrease in accumulation was attributable to an active efflux, because everted (inside-out) membrane vesicles made from tetracycline-induced E. coli cells containing any one of the four plasmids were shown to concentrate tetracycline by an active influx. This active uptake was not seen in inside-out vesicles from sensitive cells or uninduced R222-containing cells. In vesicles from induced R222-containing cells, the efflux appeared to be carrier-mediated with a Km of about 6 microM. These results demonstrate that active export of tetracycline is a common component of the mechanism for tetracycline resistance encoded by different plasmid-borne determinants in bacteria.

Biological Transport, Active↗
PubMed1996

The purified Bacillus subtilis tetracycline efflux protein TetA(L) reconstitutes both tetracycline-cobalt/H+ and Na+(K+)/H+ exchange.

Recent work has suggested that the chromosomally encoded TetA(L) transporter of Bacillus subtilis, for which no physiological function had been shown earlier, not only confers resistance to low concentrations of tetracycline but is also a multifunctional antiporter protein that has dominant roles in both Na(+)- and K(+)-dependent pH homeostasis and in Na+ resistance during growth at alkaline pH. To rigorously test this hypothesis, TetA(L) has been purified with a hexahistidine tag at its C terminus and reconstituted into proteoliposomes. The TetA(L)-hexahistidine proteoliposomes exhibit high activities of tetracycline-cobalt/H+, Na+/ H+, and K+/H+ antiport in an assay in which an outwardly directed proton gradient is artificially imposed and solute uptake is monitored. Tetracycline uptake depends on the presence of cobalt and vice versa, with the cosubstrates being transported in a 1:1 ratio. Evidence for the electrogenicity of both tetracycline-cobalt/H+ and Na+/H+ antiports is presented. K+ and Li+ inhibit Na+ uptake, but there is little cross-inhibition between Na+ and tetracycline-cobalt uptake activities. The results strongly support the conclusion that TetA(L) is a multifunctional antiporter. They expand the roster of such porters to encompass one with a complex organic substrate and monovalent cation substrates that may have distinct binding domains, and provide the first functional reconstitution of a member of the 14-transmembrane segment transporter family.

Antiporters↗
PubMed2001

Tetracycline residues in meat and bone meals. Part 2: the effect of heat treatments on bound tetracycline residues.

The stability of bound tetracycline residues during heat treatments at 133 degrees C and 100 degrees C for up to 45 min was investigated. An intermediate product from a rendering plant was mixed with bone splinters that contained bound tetracycline (TC) and chlortetracycline (CTC) residues. The mixture was heated in an autoclave at 133 degrees C for 20, 30 and 45 min and at 100 degrees C for 20 and 30 min and subsequently dried at 103 degrees C for 4 h. Two different extraction procedures with hydrochloric acid were used, one with and one without the previous sedimentation of bone particles. Tetracycline concentrations were determined by HPLC analysis before and after the heat treatment. A complete destruction of tetracyclines during heat treatment at 133 degrees C could not be demonstrated, but there was a significant decrease of TC by about 50%. CTC was less resistant to the same temperature, which brought about a reduction of 90-100%. Treatment at 100 degrees C did not bring about any reduction, except for CTC after extraction without sedimentation. The possible toxicological relevance of the findings is discussed. Further research has to be done on possible degradation products of the tetracycline derivatives.

Animals↗
PubMed1997

High-level tetracycline-resistant Neisseria gonorrhoeae in Ontario, Canada--investigation of a cluster of isolates, showing chromosomally mediated resistance to penicillin combined with plasmid-mediated resistance to tetracycline.

Between 1991 and 1994, plasmid-mediated, tetracycline-resistant Neisseria gonorrhoeae (TRNG) increased from 61.8% to 85.96% of all resistant isolates in Ontario, Canada. Ninety-nine isolates with tetracycline MICs >32 mg/L were characterized by auxotype/serovar (A/S) class, plasmid profile, hybridization with eight tetracycline-resistant probes, and pulsed-field gel electrophoresis (PFGE) of genomic DNA after digestion with NheI and SpeI restriction endonucleases. A cluster of 82 isolates with penicillin MICs of 2-4 mg/L and tetracycline MICs of 128 mg/L (chromosomally mediated resistance) belonged to A/S class NR/IB-1 and had identical or closely related PFGE profiles. Seventeen isolates, TRNG (10) and penicillinase-producing TRNG (7), with tetracycline MICs of 64-256 mg/L, belonged to eight A/S classes and displayed 12 different PFGE profiles. The 99 isolates hybridized only with the TetM probe. Phenotypic and molecular characterization indicated a diverse population throughout the Province of Ontario.

Chromosomes, Bacterial↗
PubMed1983

Amplifiable resistance to tetracycline, chloramphenicol, and other antibiotics in Escherichia coli: involvement of a non-plasmid-determined efflux of tetracycline.

Increasing levels of resistance to tetracycline and to a number of other unrelated antibiotics, including chloramphenicol, beta-lactams, puromycin, and nalidixic acid, occurred in Escherichia coli after 50 to 200 generations of growth in the presence of subinhibitory concentrations of tetracycline or chloramphenicol. In the absence of selective pressure, resistances fell to low levels within 100 generations of growth. This amplification of resistance was observed in laboratory and naturally occurring E. coli strains as well as in polA and recA strains. With the exception of previously identified cmlA and cmlB mutations, tetracycline or chloramphenicol resistances were not P1 transducible. Coincident with the emergence of resistance was the appearance of a previously cryptic energy-dependent efflux system for tetracycline. The expression of resistance phenotypes and the tetracycline efflux system were temperature sensitive at 42 degrees C.

Anti-Bacterial Agents↗
PubMed1967

Development of resistance to novobiocin, tetracycline, and a novobiocin-tetracycline combination in Staphylococcus aureus populations.

The antibiotic sensitivity of the individual organisms of a bacterial population was determined to study the comparative rates of development of resistance of Staphylococcus aureus to novobiocin, tetracycline, and to a combination of these antibiotics. Serial subculture of S. aureus with the combination of novobiocin-tetracycline (N-T 2.5:1; the ratio in serum of patients dosed with Panalba) showed a significant retardation of resistance outgrowth compared with subculture in the presence of the antibiotics individually. Increase in organisms resistant to novobiocin seen after one N-T subculture was related to the "concentration gap" between novobiocin and tetracycline. Two additional subcultures with N-T caused little or no increase in organisms resistant to novobiocin, tetracycline, or to the combination. The data suggest that the retardation of further development of resistance was the result of tetracycline inhibition of novobiocin-resistant strains and vice versa.

Drug Resistance, Microbial↗
PubMed1994

Effects of tetracycline-containing gel and a mixture of tetracycline and citric acid-containing gel on non-surgical periodontal therapy.

The purpose of this study was to assess the clinical and microbiological effects of a newly developed root conditioning gel system containing tetracycline or a mixture of tetracycline and citric acid on non-surgical periodontal therapy. Sixty-four (64) single-rooted teeth with a probing depth of 4 to 6 mm were randomly subjected to one of the following four treatments; 1) root planing alone (RP group); 2) tetracycline-containing gel alone (TCG group); 3) root planing plus tetracycline-containing gel (RP + TCG group); or 4) root planing plus a mixture of tetracycline and citric acid-containing gel (RP + TC-CAG group). Probing depth, attachment level, and tooth mobility were measured and the presence of dental plaque and gingival inflammation was recorded at baseline and after 2, 4, 8, and 12 weeks. Subgingival plaque samples from each site were collected at the same visits and examined with phase contrast microscopy for proportions of motile rods and spirochetes. Plaque index, gingival sulcus bleeding index (SBI), probing depth, and attachment level decreased significantly in all groups compared to the baseline values (P < 0.05). A significant decrease in probing pocket depth was noted after 12 weeks in RP + TC-CAG group compared to the other groups (P < 0.05). Significantly more gain in attachment was detected in the RP + TC-CAG group compared to the TCG group (P < 0.05). Tooth mobility scores also decreased later in the study. A significant decrease in the proportion of motile rods was found primarily in the RP + TC-CAG group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1968

Comparison of side-effects of tetracycline and tetracycline plus nystatin. Report to the Research Committee of the British Tuberculosis Association by the Clinical Trials Subcommittee.

In a multicentre, double-blind, controlled trial of tetracycline plus nystatin (Mysteclin) and tetracycline, 111 patients with respiratory infections received one or other drug for a period of 10 days.The incidence of gastrointestinal symptoms was high in both groups before treatment began, and somewhat higher in the Mysteclin group than in the tetracycline group. After 10 days' treatment 50% of the patients in the Mysteclin group had symptoms, a mean of 1.44 each, compared with 34% of the patients in the tetracycline group, with a mean of 1.47 symptoms each; the difference between the two groups is not significant (P>0.05). The incidence of Candida albicans in the stools at 10 days in the Mysteclin group (9.1%) was significantly lower than that in the tetracycline group (37.1%), but this was not reflected in any reduction in the frequency of gastrointestinal symptoms.

Candida↗
PubMed1995

[Generation of active forms of oxygen by antibiotics of the tetracycline series during tetracycline catalysis of oxidation of ferrous iron].

During oxidation of Fe(2+) catalyzed by tetracyclines there was recorded lucigenin, activated chemiluminescence evident of generation of the oxygen radicals. It was also observed that during the Fe(2+) oxidation by the molecular oxygen catalyzed by tetracyclines there generated hydrogen peroxide which accelerated the Fe(2+) oxidation recorded photometrically by the formation of strongly absorbing tetracycline complexes with Fe(2+). In the presence of ascorbate reducing Fe(2+) in the complexes with tetracyclines and their subsequent oxidation there generated radicals modifying the antibiotic molecules evident from a change in their absorption spectra after the respective incubation. The results offered a pattern describing the mechanism of the tetracycline toxic effect on biological objects.

Acridines↗
PubMed1997

Delay in resumption of the activity of tetracycline-regulatable promoter following removal of tetracycline analogues.

The tetracycline-regulatable system (TRS) has become a widely adopted tool for modification of gene expression and analysis of gene function in mammalian cells, plants and transgenic animals. We have studied the potential application of the TRS in gene therapy, using a single vector containing both the tetracycline-controlled transactivator (tTA) and the tTA-responsive promoter (tRP) transcribing mouse GM-CSF. Stable 293 cells established using this vector were used to study the kinetics of the TRS in response to various tetracycline analogues. Dose-response studies show that doxycycline is the most potent-analogue in abolishing tTA activity. Kinetic studies indicate that, at 1,000 ng/ml, all the analogues have similar efficiencies in down-regulating the system in given time. In contrast, following the removal of the analogues, there is a temporal, dose-dependent delay in resumption of the tRP activity. The time taken for resumption of near-optimal tRP activity is approximately 48 h for tetracycline, 144 h for anhydrotetracycline, 192 h for minocycline and 216 h for doxycycline when cells were pretreated with 1000 ng/ml of these antibiotics. This property of the analogues can be employed in planning a desired course of transgene regulation.

Animals↗
PubMed1993

A new tetracycline resistance determinant, Tet H, from Pasteurella multocida specifying active efflux of tetracycline.

The tetracycline resistance determinant on plasmid pVM111 from an avian strain of Pasteurella multocida mediates tetracycline resistance by a regulated active efflux mechanism. DNA coding for the determinant did not hybridize at high stringency with DNA representing a group of common tetracycline resistance determinants. The DNA sequence, however; revealed a structural gene and a repressor gene which had significant (37 to 64%) sequence similarities with previously described classes of efflux-type tetracycline resistance genes from members of the family Enterobacteriaceae. The new determinant has been assigned to class H.

Amino Acid Sequence↗
PubMed2000

A direct photo-activated affinity modification of tetracycline transcription repressor protein TetR(D) with tetracycline(1).

Results of a first successful application of a direct photo-induced affinity modification of Tet repressor (TetR(D)) protein with tetracycline within a complex of known three-dimensional structure are described. The conditions of the modification have provided suitable yields of the modified complex and allowed characterization of the modified segments of the protein. The potential of tetracycline as a fine modifying reagent was established. In the complex of TetR(D) protein with tetracycline, the antibiotic modifies at least two segments, Ile59-Glu73 and Ala173-Glu183, which form a binding tunnel for the drug according to the X-ray analysis. These data open possibilities for the use of different tetracycline targets for structural studies in solution.

Amino Acid Sequence↗
PubMed1973

Effect of oral tetracycline on the occurrence of tetracycline-resistant strains of Escherichia coli in the intestinal tract of humans.

Serial samples of feces from normal human subjects were analyzed for tetracycline-resistant strains of Escherichia coli. Subjects were found to be excreting tetracycline-resistant strains in amounts fluctuating with time. Ingestion of tetracycline increased both the number of individuals excreting tetracycline-resistant strains of E. coli and the proportion of the total E. coli isolates resistant to the antibiotic.

Administration, Oral↗
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↗
PubMed1983

[Demonstration of a tetracycline-resistance factor in a genital Mycoplasma strain. Clinical and molecular biology aspects of Ureaplasma coinfected penicilliń and tetracycline-resistant gonorrhea].

We report a male patient with severe penicillin-resistant gonococcal urethritis, coinfected with a tetracycline resistant strain of ureaplasma urealyticum. Ureaplasmas are frequently involved in gonococcal urethritis and commonly this organism may persist after the penicillin therapy causing a "post-gonoccal-urethritis" (PGU). Additional treatment with tetracyclines prove to be successful in most of these patients except in cases of tetracycline resistance in ureaplasma urealyticum. In a case like this erythromycin may be useful, a drug to which these isolates are sensitive. The microbiological and genetic feature of a tetracycline resistant strain of ureaplasma urealyticum is presented in detail. The clinical and epidemiological importance of these results are discussed and compared with the literature.

Adult↗