Natural tetracyclines

Treatment of 14 with hydrogen and a catalyst converts it to a mixture of epimeric 6-deoxy-5-oxytetracyclines (15 and 16), each of which is active as an antibiotic. The more active isomer has the natural tetracycline configuration of the methyl group at Ce and is in clinical use as a 6-deoxyoxytetracycline (15). ... 

A series of tetracycline derivatives has recently been isolated from species of Dactylosporangium. These compounds, the dactylocyclines (Figure 3.55), are glycosides and have the opposite configuration at C-6 to the natural tetracyclines. Importantly, these compounds are active towards tetracycline-resistant bacteria. 

The X-ray diffraction studies reveal that the following stereochemical formula represents the orientations, as observed in the natural tetracyclines ... 

Drugs of the tetraeycline group are amphoteric, forming salts with both acids and bases. They are used as parent compounds (e.g., oxytetracycline dihydrate) or as salts (e.g., oxytetracycline hydrochloride). Their lipid solubilities range from moderate (oxytetracycline and chlortetracycline) to high (doxycycline and minocycline), so that they are able to traverse cell membranes moderately or readily. The former two drugs are natural tetracyclines, while the latter two are semi-synthetic. 

Chlortetracycline from Streptomyces aureofackns was the first tetracycline to be isolated, in 1948. Since that time there have been more than 30 new natural tetracyclines, mainly isolated from Streptomyces species, including oxytetracycline in 1950 and tetracycline in 1953 (44). Most natural tetracyclines have a common structure (Figure 1) with the 3-diketone system in rings B and C essential for antibiotic activity. Some natural tetracyclines such as terramycin X have the acetomido-group at C2 replaced by an acetyl-group, and democycline and demecycline lack the methyl-group at C6 (Table 1). 

An on-line concentration, isolation, and Hquid chromatographic separation method for the analysis of trace organics in natural waters has been described (63). Concentration and isolation are accompHshed with two precolumns connected in series the first acts as a filter for removal of interferences the second actually concentrates target solutes. The technique is appHcable even if no selective sorbent is available for the specific analyte of interest. Detection limits of less than 0.1 ppb were achieved for polar herbicides (qv) in the chlorotriazine and phenylurea classes. A novel method for deterrnination of tetracyclines in animal tissues and fluids was developed with sample extraction and cleanup based on tendency of tetracyclines to chelate with divalent metal ions (64). The metal chelate affinity precolumn was connected on-line to reversed-phase hplc column, and detection limits for several different tetracyclines in a variety of matrices were in the 10—50 ppb range. 

Efforts have been made to correlate electronic stmcture and biological activity in the tetracycline series (60,61). In both cases, the predicted activities are of the same order as observed in vitro with some exceptions. The most serious drawback to these calculations is the lack of carryover to in vivo antibacterial activity. Attempts have also been made (62) to correlate partition coefficients and antibacterial activity. The stereochemical requirements are somewhat better defined. Thus 4-epitetracycline and 5a-epitetracycline [65517-29-5] C22H24N20g, are inactive (63). The 6-epi compound [19369-52-9] is about one-half as active as the 6a (or natural) configuration. 

The tetracyclines are a group of anti-infectives composed of natural and semisynthetic compounds. They are useful in select infections when die organism shows sensitivity (see Chap. 7) to the tetracyclines, such as in cholera, Rocky Mountain spotted fever, and typhus. 

Many natural aromatic compounds are produced from the cyclization of poly- -keto chains by enzymic aldol and Claisen reactions. Examples include simple structures like orsellinic acid and phloracetophenone, and more complex highly modified structures of medicinal interest, such as mycophenolic acid, used as an immunosuppressant drug, the antifungal agent griseofulvin, and antibiotics of the tetracycline group, e.g. tetracycline itself. 

The quinolone antibiotics feature as the one main gronp of antibacterial agents that is totally synthetic, and not derived from or based upon natural products, as are penicillins, cephalosporins, macrolides, tetracyclines, and aminoglycosides. The first of these compounds to be employed clinically was nalidixic acid more recent drugs in current use include ciprofloxacin, norfloxacin, and ofloxacin... 

The practice of incorporating low levels of antibiotics in livestock feeds to promote growth has been particularly controversial. It is feared that this practice will result in development of resistant bacteria in animals, which will in turn be passed on to humans, thus diminishing the effectiveness of antibiotics in treatment of human disease. A petition from the Natural Resources Defense Council to ban such uses of penicillin and tetracyclines recently was denied by the Secretary of Health and Human Services. The controversy therefore is likely to continue. Opinion on the subject is quite polarized, and several points of view are presented in this book. 

Ahmed A. K. S. Chasis and B. McBarnette. Petition of the Natural Resources Defense Council Inc. to the Secretary of Health and Human Services requesting immediate suspension of approval of the subtherapeutic use of penicillin and tetracyclines in animal feeds" Nov. 20. NRDC New York NY. 1984. 

Long-term, low-level feeding of penicillin and the tetracyclines promotes, by natural selection from the pool of normal intestinal flora, those enteric (gut) bacteria that contain R-plasmids. R-plasmids, also known as R-factors, are extrachromosomal genetic material which confer antibiotic resistance to host bacteria. These plamids can be transferred between various kinds of bacteria through cell-to-cell contact (conjugation). Simultaneous resistance to several unrelated antibiotics is commonly carried on a single plasmid and therefore is simultaneously transferred from one bacterium to another. 

On November 20, 1984, Secretary Heckler received from the Natural Resources Defense Council (NRDC) a petition to declare the subtherapeutic uses of penicillin and the tetracyclines in animal feeds an imminent hazard to the public health. NRDC argues that, on the basis of three recently published scientific studies—the O Brien and the two Holmberg studies discussed earlier—FDA is likely to eventually withdraw approval of the subtherapeutic uses of penicillin and the tetracyclines in animal feeds. NRDC argues, based on these studies, that these uses meet the criteria for imminent hazard under the law. The petition and its impact were discussed before Congress, in hearings before the Committee on Science and Technology in December of 1984 (15). 

As a group, the protein biosynthesis inhibitors comprise the second largest class of antibiotics available for clinical use. Natural product classes of antibiotics that inhibit the protein biosynthesis are aminoglycosides, tetracyclines, chloramphenicol, macrolides, lincosamides, fusidic acid, streptogramins and mupirocin (Fig. 7). 

Another group of compounds, the tetracyclines, are made by fermentation procedures or by chemical modifications of the natural product. The hydrochloride salts are used most commonly for oral administration and are usually encapsulated because of their bitter taste. Controlled catalytic hydrogenolysis of chlortetracycline, a natural product, selectively removes the 7-chloro atom and produces tetracycline. Doxycycline and minocycline are other important antibacterials. Tetracycline can be prescribed for people allergic to penicillin. Doxycycline prevents traveler s diarrhea. Tetracyclines help many infections including Rocky Mountain spotted fever, Lyme disease, urinary tract infections, bronchitis, amoebic dysentery, and acne. 

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