Tetracycline

11 Key excerpts on "Tetracycline"

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  Protein Synthesis: Methods and Protocols

  • Bhupendra Pushkar(Author)
  • 2020(Publication Date)
  • Delve Publishing

    (Publisher)

  7.3.3. Tetracyclines The Tetracycline type of antibiotics is supposed to be belonging from a huge family of broad spectrum, bacteriostatic agents consisting of limited, however, vital role in the armamentarium of bacterial agents. In 1950s, Tetracycline is considered to be the product of a soil-screening program to detect antimicrobials. Chemical Structure: The primary structure would be consisting of four bonded 6-carbon rings. The activity of various members of the type would be created through modifying at designated carbon sites. Mechanism of Action: The 30S ribosome would be the major target which would prevent the binding of aminoacyl tRNA to the acceptor (A) site on mRNA. Mechanism of Resistance: The chief mechanism of resistance to Tetracyclines would be low or high export of the drug through efflux pumps. The mechanism might be considered as plasmid mediated as well as gives resistance to every member of the group. Protein Synthesis: Methods and Protocols 190 Antibacterial spectrum: Though such drugs would have Gram-positive activity, inclusive of pneumococcus, streptococci and enterococci, yet, they would be seldom used due to their resistance. They would possess activity in opposition to Gram-negatives – E. coli , however, excluding other Enterobacteriaceae, Neisseria, Hemophilus as well as few Shigella. Even they would be active against mycoplasma, rickettsia, legionella, spirochetes and chlamydia. Pharmacology: Maximum Tetracyclines would be given orally. Both short and long acting agents would exist. A greater number would include lipophilic with brilliant tissue distribution. The most frequently used Tetracyclines, like minocycline (metabolized in the liver) and doxycycline (inactivated in the intestine), would be removed through non-renal tracks. Toxicity: Though, the toleration level is usually good, yet, it would have an index of major side effects.

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  Bacterial Resistance to Antibiotics

  From Molecules to Man

  • Boyan B. Bonev, Nicholas M. Brown, Boyan B. Bonev, Nicholas M. Brown(Authors)
  • 2019(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  5 Tetracyclines : Mode of Action and their Bacterial Mechanisms of Resistance

  Marilyn C. Roberts

  Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA

  5.1 Introduction of Tetracyclines

  Tetracyclines are one of the oldest classes of antibiotics used and the first broad spectrum class of antibiotics. Tetracyclines interact with the bacterial ribosomes by reversibly attaching to the ribosome that blocks protein synthesis. The first generation compounds, chlorTetracycline discovered in 1945 followed by oxyTetracycline in 1950, and Tetracycline in 1953. ChlorTetracycline was first isolated from the soil microbe Streptomyces aureofaciens in 1948 [1] . The core structure includes a four‐ring system labeled A–D where rings A–C include saturated carbon centers and ring D is aromatic. Bacterial resistance of the first generation lead to the development of chemically modified derivatives with better pharmacological properties, including doxycycline in 1967 and minocycline in 1972. Meta‐substitution of ring D resulted in the third generation of Tetracycline, tigecycline, which was approved by Food and Drug Administration (FDA) in 2005 and Europe in 2006 [2] .

  Minocycline has better pharmacokinetic profiles and a longer half‐life than Tetracycline. It has excellent tissue penetration and high levels of bioavailability and is now more often used than Tetracycline in human medicine. Other derivatives such as oxyTetracycline are often used in animals. Tetracyclines have been prescribed at low dosage for long term use (>10 years) for acne vulgaris and is generally well tolerated. Tetracyclines are able to pass through the blood–brain barrier and thus can be used to treat central nervous system (CNS

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  Pharmacology and Therapeutics for Dentistry - E-Book

  Pharmacology and Therapeutics for Dentistry - E-Book

  • Frank J. Dowd, Bart Johnson, Angelo Mariotti(Authors)
  • 2016(Publication Date)
  • Mosby

    (Publisher)

  Table 33-10 ).

  Mechanism of action

  Tetracyclines inhibit bacterial protein synthesis by preventing the association of aminoacyl-tRNA with the bacterial ribosome . The drugs must transverse the gram-negative microbial outer membrane via porin channels or through the gram-positive cell wall in its electronegative hydrophobic form and attach to a single high-affinity binding site on the ribosomal 30S subunit and protein 7 on the 16S rRNA base.

  Bacterial resistance

  Microbial resistance to Tetracyclines is widespread, transposable, inducible, and commonly permanent because their resistance genes are almost always combined in transposable elements with the genes for resistance to other antibiotics (multidrug resistance gene cassettes). Of the three mechanisms for Tetracycline resistance (drug efflux, ribosomal protection, and enzymatic inactivation), drug efflux is the most important, with at least 300 different active efflux proteins capable of extruding Tetracycline from the bacterial cell.

  Tetracyclines are one of the most active chemical inducers of microbial resistance gene expression and downregulate a repressor gene that controls efflux activity for not only Tetracyclines but also possibly other antibiotics. Only nanomolar amounts of Tetracycline are necessary to de-repress this system and greatly increase antibiotic efflux from bacterial cells. Tetracyclines also promote the mobility of resistance determinants (transfer of resistance genes between bacteria) by stimulating the frequency of bacterial conjugation. Considering these extraordinary properties of Tetracyclines to induce and promote microbial resistance not only to themselves but also other antibiotics, it would seem prudent to restrict their use to serious medical infections and restrict their use in most cases of periodontitis, where they may have limited or even undocumented value.

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  Antimicrobial Pharmacodynamics in Theory and Clinical Practice

  • Charles H. Nightingale, Paul G. Ambrose, George L. Drusano, Takeo Murakawa, Charles H. Nightingale, Paul G. Ambrose, George L. Drusano, Takeo Murakawa(Authors)
  • 2007(Publication Date)
  • CRC Press

    (Publisher)

  The interest and common use of pharmaco-dynamics began after development of the early generation Tetracyclines. Thus, it was not until the recent development of the new glycylcycline derivatives that most of the work detailing the pharmacodynamic characteristics of this class has been undertaken. MECHANISM OF ACTION Tetracyclines reversibly inhibit bacterial protein synthesis by binding to the ribosomal complex (15,19). The 30s ribosomal subunit is the binding target for these compounds. Drug binding to the ribosome prevents the entry of aminoacyl-transfer RNA to the A site of the ribosome. Inhibition of this interaction prohibits incorporation of amino acids onto elongating peptide chains. SPECTRUM OF ACTIVITY The Tetracyclines have broad-spectrum activity, which includes gram-positive and gram-negative bacteria, atypical respiratory pathogens, rickettsiae, spirochetes, and some parasites (3 – 5,15). In general, among the commonly available tetracy-cline compounds, the relative order of potency against gram-positive bacteria is 267 minocycline > doxycycline > Tetracycline. The gram-positive spectrum includes most Staphylococcus aureus, many S. epidermidis, and most streptococci. Activity against methicillin-resistant S. aureus , b -lactam – resistant pneumococci, and enter-ococcal species is limited. Activity against gram-negative bacteria is more variable. The class demonstrates intrinsic activity against many common nosocomial gram-negative organisms such as Escherichia coli and Klebsiella spp. However, the emergence of resistance has rendered the class ineffective as an empiric option in therapy targeted toward these pathogens. Still, Tetracyclines remain potent against a wide spectrum of gram-negative species encountered in the community includ-ing Yersinia pestis , Vibrio cholera , Francisella tularensis, Pasteurella multocida , and Haemophilus ducreyi . The common intracellular bacteria Mycoplasma pneumoniae and all Chlamydia spp.

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  Thin Layer Chromatography in Drug Analysis

  • Lukasz Komsta, Monika Waksmundzka-Hajnos, Joseph Sherma(Authors)
  • 2013(Publication Date)
  • CRC Press

    (Publisher)

  Despite this, they remain the treatment of choice for some specific indications. Tetracyclines exert a bacteriostatic effect on bacteria by binding reversible to the bacterial 30S ribosomal subunit and blocking incom-ing aminoacyl tRNA from binding to the ribosome acceptor site. They also bind to some extent to the bacterial 50S ribosomal subunit and may alter the cytoplasmic membrane causing intracellular components to leak from bacterial cells. Tetracyclines are generally used in the treatment of infec-tions of the respiratory tract, sinuses, middle ear, urinary tract, and intestines, especially in patients allergic to β -lactams and macrolides. They remain the treatment of choice for infections caused by chlamydia (trachoma, psittacosis, salpingitis, urethritis, and Lymphogranuloma venereum infec-tion), rickettsia (typhus, Rocky Mountain spotted fever), brucellosis, and spirochetal infections (borreliosis, syphilis, and Lyme disease). In addition, they may be used to treat anthrax, plague, tularemia, and Legionnaires’ disease. They are also used in veterinary medicine on pigs and alike. 48.1.1 S EPARATION AND D ETERMINATION OF T ETRACYCLINES Crecelius et al. analyzed Tetracyclines using different particle suspensions by TLC–MALDI– TOF-MS. The majority of the results were obtained for a suspension of graphite in ethylene glycol that was found to yield better sensitivity in comparison to the other tested materials and dispersants. Extracted ion chromatograms have been constructed from the TLC–MALDI analysis of chlortetra-cycline, Tetracycline, oxyTetracycline, and minocycline. Calculation of the R F value of the detected spots showed good agreement with the R F values obtained by ultraviolet (UV) detection. Pretreatment of the aluminum-backed silica gel 60 F 254 TLC plates was necessary in order to avoid the forma-tion of metal–Tetracycline complexes and hence to improve the separation.

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  International Congress for Microbiology

  Moscow, 1966

  • Sam Stuart(Author)
  • 2014(Publication Date)
  • Pergamon

    (Publisher)

  Tetracycline does not bind to purified ribosomes of Escherichia coli (Last et al. 1965). A reported binding of the antibiotic to the 30s subunit of ribosomes of Bacillus cereus may actually have been due to a binding of the antibiotic to messenger RNA remaining on these ribosomes (Connamacher and Mandel, 1965). Tetracycline apparently forms a molecular complex with poly U (Connamacher and Mandel, 1965), and we have found (Wolfe and Hahn, 1966) that oxyTetracycline-Mn actually precipitates poly U while the magnesium chelate of the antibiotic precipitates poly A. An interaction of Tetracycline chelates with messenger RNA on the ribosome may be responsible for recent observations that Tetracyclines inhibit the messenger-directed binding of amino acyl transfer RNAs to ribosomes (Hierowski, 1965). For a given concentration of Tetracycline, this binding reaction is approximately one half as sensitive to inhibition as is the polymerization of amino acids in a corresponding amino acid incorporation system (Suarez and Nathans, 1965). This observation has invited speculation that the antibiotic obstructs one of two binding sites on the ribosome concerned with the attachment of transfer RNA. Proof of the correctness of this hypothesis comes from observations (Suzuka and Kaja, 1966) that Tetracycline inhibits the specific binding of one transfer RNA molecule to the 30s ribosomal subunit but has much less effect upon the subsequent binding of a second transfer RNA molecule to a second site which is generated by combining the 30s and 50s subunits and thus reconstituting a standard 70s ribosome. An inhibition by Tetracyclines of the messenger-directed binding of incoming amino acyl transfer RNA to the ribosome appears to be the most likely explanation of the mechanism of action of this group of antibiotics. Chloramphenicol but not its three stereoisomers (Fig. 5) inhibits cell-free ribosomal systems of protein synthesis (Rendi and Ochoa, 1962).

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  Structural Aspects of Protein Synthesis

  • Anders Liljas, Måns Ehrenberg(Authors)
  • 2013(Publication Date)
  • WSPC

    (Publisher)

  et al., 1999).

  10.2  INHIBITORS OF AMINOACYL-tRNA BINDING

  Tetracycline

  Tetracycline (Fig. 10.3) has been used extensively since the 1940s as a ‘broad-spectrum’ antibiotic, in both human and veterinary medicine (Chopra et al., 1992). This has lead to widespread resistance (Salyers et al., 1990; Taylor & Chau, 1996). Tetracycline has one strong binding site on the small ribosomal subunit in addition to several weaker ones (Epe et al., 1987; Kolesnikov et al., 1996). The strong binding site is between the head and shoulder of the small subunit near the position of the anticodon-stem-loop (ASL) of the A-site (Brodersen et al., 2000; Pioletti et al., 2001). Tetracycline binds to helix h34 (residues 1054–1056 and 1196–1200) and helix h31 (residues 964–967) at the A-site (Maxwell, 1967; Geigenmuller & Nierhaus, 1986). It inhibits neither the binding of the ternary complex with its tRNA to the A/T-site (see Sec. 9.3) nor the dissociation of EF-Tu after GTP hydrolysis (Gordon, 1969). However, it prevents aminoacyltRNA from accommodating into the A-site (Wilson, 2004). Since the aminoacyl-tRNA therefore dissociates, one effect of Tetracycline binding to the ribosome is that the GTP pool of the cell gets depleted (Brodersen et al., 2000). Tetracycline also inhibits the binding of release factors RF-1 and RF-2 to the ribosome (Brown et al., 1993).

  Fig. 10.3 Tetracycline (drawn by Andreas Ehnbom).

  The secondary binding sites probably have no inhibitory effects, but it was noticed that one of them is close to h27, h44 and h11 (Brodersen et al., 2000; Pioletti et al., 2001). This location may affect accuracy (Lodmell & Dahlberg, 1997).

  Resistance against Tetracycline is gained by a mutation, G1058C, in the immediate proximity of the primary binding site for Tetracycline on the 16S RNA (Ross et al., 1998). Another type of resistance is due to ribosomal protection proteins, Tet(M) and Tet(O), which are homologues of EF-G (Burdett, 1996; Trieber et al., 1998; Dantley et al.

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  Experimental Chemotherapy V3

  • R Schnitzer(Author)
  • 2013(Publication Date)
  • Academic Press

    (Publisher)

  Although the close chemical relationship of the Tetracycline antibiotics sug-gests that their antibacterial activity would be similar it cannot be assumed that their mode of action is identical and at present the mode of action of none of them is understood. A number of specific reactions have been described, however, and these will be briefly summarized. Gale and Folkes ( 1 9 5 3 ) showed that sub-bacteristatic concentrations ( 0 . 2 -0 . 4 ig./m.) of ChlorTetracycline and Oxytetra-cycline inhibited protein synthesis by 5. aureus, whereas inhibition of nucleic acid synthesis and accumulation of free glutamic acid only occurred with very much higher concentrations ( 5 0 μg./ml. ChlorTetracycline and 3 0 0 μg./ml. Oxy-Tetracycline). Many oxidation and fermentation reactions are also inhibited by the Tetracyclines but for the most part only in high concentrations, although there is some evidence to suggest that bacterial respiration is more readily inhibited if the bacterial cells are in the logarithmic phase of growth (see Eagle and Saz, 1 9 5 5 ) . Finally, mention must be made of the affinity of the Tetracyclines for di- and trivalent metals, by which means they may interfere with many enzyme systems in mammalian and bacterial cells (see Albert, 1 9 5 3 ; Albert and Rees, 1 9 5 6 ; Albert et al., 1 9 5 6 ) . Thus ChlorTetracycline has been shown to inhibit phosphory-lation in normal mitochondria (Loomis, 1 9 5 0 ) , in rat liver and brain (Brody and Bain, 1 9 5 1 ) , and in a cell-free preparation of organic nitroreductase ex-tracted from Escherichia coli (Saz and Marmur, 1 9 5 3 ) . It is of interest that the latter reaction was not inhibited under similar conditions by OxyTetracycline. Some of these actions as well as the antibacterial activity of the Tetracyclines are inhibited by the addition of the cations Fe 3 +, Mg 2 +, and Mn 2 + (Van Meter et al, 1 9 5 2 ; Brody et al, 1 9 5 4 ; Weinberg, 1 9 5 4 ) .

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  Structural Aspects Of Protein Synthesis (2nd Edition)

  • Anders Liljas, Mans Ehrenberg(Authors)
  • 2013(Publication Date)
  • World Scientific

    (Publisher)

  10 Inhibitors of Protein Synthesis — Antibiotics, Resistance Numerous compounds inhibit protein synthesis (Vazquez, 1974). Many of them are known to bind to the ribosome. The inhibitors are to a large extent natural products isolated from different microorganisms, which excrete these antibiotics in their fight for living space. The antibiotics can kill bacteria and are then bacterio-cidal, but most antibiotics inhibit bacterial reproduction and are therefore bacteriostatic. A number of antibiotics, which target the protein synthesis machinery, are clinically used since they selec-tively inhibit certain bacteria. Normally, an organism is resistant to the antibiotics it pro-duces. Thus, the resistance mechanism must have coevolved with the antibiotics with the potential of spreading to other organisms. The microbial resistance to antibiotics has become a serious and growing health problem (Chopra, 2000; Woodford & Livermore, 2009). The search for new synthetic or semi-synthetic inhibitors and antibiotics for which there are no resistance mechanisms is therefore a major effort (Knowles et al. , 2002; Franceschi & Duffy, 2006; Skripkin et al ., 2008). An inhibitor acts like a ‘spanner in the works’ (Spahn & Prescott, 1996). In the ribosome, an antibiotic may inhibit a functional process by binding to an essential binding site or by changing the functional 229 dynamics of the machinery in such a way that the transition to the next state is blocked (Table 10.1; Fig. 10.1). Thus, like in the studies of other enzymes, the analyses of inhibitors and the resistance against them provide good means of understanding the underlying function (Blaha et al ., 2012). Since the functional sites of the ribosome are primarily composed of rRNA, it is not surprising that antibiotic binding sites are generally located on the rRNA (Cundliffe, 1987, 1990). As there usually are multiple genomic copies of the rRNAs, mutations of the rRNAs rarely lead to resistance.

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  Antimicrobial Drug Resistance

  • L Bryan(Author)
  • 2012(Publication Date)
  • Academic Press

    (Publisher)

  B. Development of Drugs Particular to Resistant Strains Most suggestions for development of newer Tetracycline antibiotics have focused on improved absorption without loss of activity. A prodrug that will be absorbed well and that can then be converted in vivo to a more active Tetracycline is such a candidate. However, such a drug would still be ineffective against resistant organisms. The actual benefit from this kind of improvement would, therefore, be limited. A different pharmaco-logic approach would move from trying to enhance basic activity to find-ing a derivative particularly useful against resistant bacteria. Such a drug could be one unaffected by the resistance mechanism. Another approach is to find an agent that would enhance the activity of the Tetracyclines against resistant organisms. 234 STUART Β. LEVY The Tetracyclines were a boon to antimicrobial therapy. Their effective-ness has been largely curtailed by the emergence of resistant organisms. The mechanism for resistance appears to be nondegradative for a large number of different species examined. This has led to accumulation of active drug in the environment. A major component of resistance is active efflux of the drugs. Another proposed component is sequestration in inac-tive sites in the cell. A ribosomal change may yet be found for some of the resistant streptococcal strains. While the widespread distribution of tetra-cycline resistance determinants in nature might suggest obsolescence of the drug, it is still effective in many diseases. This situation must be safeguarded by the effective and discriminant use of these drugs in all areas of present application: humans, domestic animals, plants, and com-mercially valuable insects. ACKNOWLEDGMENTS Work quoted from my laboratory was supported through grants from the American Can-cer Society and The National Institutes of Health. I thank all those who shared their results prior to publication.

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  Medicinal Chemistry—III

  Main Lectures Presented at the Third International Symposium on Medicinal Chemistry

  • P. Pratesi(Author)
  • 2013(Publication Date)
  • Butterworth-Heinemann

    (Publisher)

  These inhibitors might be expected to block correct initiation of protein synthesis ; in fact this mode of action has already been reported for some of these antibiotics. INHIBITORS OF THE ELONGATION CYCLE Inhibitors of aminoacyl-tRNA binding The best known inhibitors of aminoacyl-tRNA binding to the ribosome are shown in Table 5. Included in this Table are edeine A ^ aurintricarboxylic acid, poly(dextran sulphate) and polyvinyl sulphate) which, as indicated above, block interaction codon-anticodon to both A- and Ρ-sites of the smaller subunit. On the other hand the Tetracycline group of antibiotics specifically block codon-anticodon interaction at the Α-site of the smaller subunit. A number of antibiotics included in the siomycin group have been shown to block aminoacyl-tRNA binding to bacterial ribosomes at the level of the 50S subunit. Fusidic acid forms the complex fusidic acid-EF-G (or EF-2)-ribosome-GDP which prevents under certain conditions translocation (see Table 8) but also aminoacyl-tRNA binding to the larger ribosomal subunit of either bacterial or eukaryotic ribosomes. It is interesting to quote that fusidic acid has been reported to have no effect on Neurospora mitochondrial systems 1 9 . Some of the inhibitors of peptide bond formation have been shown to block binding of the terminal CCA-aminoacyl to the acceptor-site of the peptidyl transferase centre (Table 7) and might be considered not only as inhibitors of peptide bond formation but also as inhibitors of aminoacyl-tRNA binding at the level of the larger ribosomal subunits. Inhibitors of peptide bond formation The antibiotic puromycin is a structural analogue of the 3'-aminosyl-adenosine moiety of aminoacyl-tRNA; therefore puromycin acts on the Α-site of the peptidyl transferase centre of prokaryotic and eukaryotic ribosomes forming a peptide bond with the initiator amino acid and blocking the correct peptide bond formation.

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