Tetracyclines chemically modified

Speer BS, Salyers AA. Novel aerobic tetracycline resistance gene 75. that chemically modifies tetracycline. 1. Bacteriol. 1989 171(1) 148-153. 

Golub LM, McNamara TF, D Angelo G, Greenwald RA, Ramamurthy NS. A non-antibacterial chemically-modified tetracycline inhibits mammalian coUagenase activity. J Dent Res 1987 66(8) 1310-14. 

The successes achieved in the past decade with chemically modified penicillins, tetracyclines, and lincomycin, undoubtedly influenced the judgment of the panel that preparation of structural analogs of useful antibiotics by chemical or other means should be ranked as one of the two most promising discovery approaches for the next decade. Before proceeding further with the evaluation made by the respondents of the five approaches (Table VII), some aspects of the history and nature of the structural modification approach are examined. 

In addition, they inhibit synthesis and release of IL-ip, IL-6, and TNFa. The future of rosacea therapy may be based on the use of chemically modified tetracyclines (CMT). 

Incubation of rat mesangial cells with chemically modified tetracyclines resulted in a time- and dose-dependent inhibition of NO production that was maximal at 48 h (<20% of control) and at a drug concentration of 5 ptg/ml (P <0.05) associated with parallel alterations in steady-state iNOS mRNA abundance and protein expression (Trachtman et al. 1996). 

Reports of the non-antimicrobial effects of tetracyclines continue to appear, and the clinical uses of non-antimicrobial tetracyclines in dermatology have been highlighted [119 ]. In general, when these drugs are used for non-infectious conditions, adverse reactions seem to be of same types and frequencies as when they are used as antimicrobial agents. However, the adverse effects profiles of the chemically modified tetracyclines have still not been properly elucidated. 

Ribosomal Protein Synthesis Inhibitors. Figure 3 The chemical structure of tetracycline and possible interactions with 16S rRNA in the primary binding site. Arrows with numbers indicate distances (in A) between functional groups. There are no interactions obseived between the upper portion of the molecule and 16S rRNA consistent with data that these positions can be modified without affecting inhibitory action (from Brodersen et al. [4] with copynght permission). 

Although all tetracyclines have a similar mechanism of action, they have different chemical structures and are produced by different species of Streptomyces. In addition, structural analogues of these compounds have been synthesized to improve pharmacokinetic properties and antimicrobial activity. While several biological processes in the bacterial cells are modified by the tetracyclines, their primary mode of action is inhibition of protein synthesis. Tetracyclines bind to the SOS ribosome and thereby prevent the binding of aminoacyl transfer RNA (tRNA) to the A site (acceptor site) on the 50S ri-bosomal unit. The tetracyclines affect both eukaryotic and prokaryotic cells but are selectively toxic for bacteria, because they readily penetrate microbial membranes and accumulate in the cytoplasm through an energy-dependent tetracycline transport system that is absent from mammalian cells. 

Antibiotics represent a chemically quite heterogenous category of compounds, for which the Cl 8 phases appear sorbents of the first choice. A group of these compounds (tetracyclines) was successfully separated by open tubular capillary electrochromatography using Cl8 modified capillaries. The results reported to be obtained in this system were better than those obtained with either monolithic columns or open diol columns [123] (Fig. 10.26). 

Robinson expressed this skepticism (45) when he wrote in 1953 .. . indeed one of the disappointments in antibiotic work is that it seems impossible to modify the molecule without reducing or eliminating its antimicrobial activity. . . The discoveries early in the 1950 s of tetracycline and phenoxymethylpenicillin established beyond doubt, however, that modification of antibiotics by chemical or biosynthetic means could yield superior drugs. 

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