The tetracyclines (Table 3.3) are a group of broad spectrum, orally active antibiotics produced by cultures of Streptomyces species. Chlortetracycline isolated from Streptomyces aureofaciens was the first of the group to be discovered, closely followed by Oxytetracycline from cultures of S. rimosus. Tetracycline was found as a minor antibiotic in S. aureofaciens, but may be produced in quantity by utilizing a mutant strain blocked in the chlorination step b (Figure 3.54). Similarly, the early C-6 methylation step (included in a) can also be blocked, and such mutants accumulate 6-demethyltetracyclines, e.g. demeclocycline (demethylchlorotetracycline). These reactions can also be inhibited in the normal strain of S. aureofaciens by supplying cultures with either aminopterin (which inhibits C-6 methylation) or mercaptothiazole (which inhibits C-7 chlorination). Oxytetracycline from S. rimosus lacks the chlorine substituent, but has an additional 5a-hydroxyl group, probably introduced at a late stage. Only minor alterations can be made to the basic tetracycline structure to modify the antibiotic activity, and these are at positions 5, 6, and 7. Other functionalities in the molecule are all essential to retain activity. Semi-synthetic tetracyclines used clinically include methacycline, obtained by a dehydration reaction from oxytetracycline, and doxycycline, via reduction of the 6-methylene in methacycline. Minocycline contains a 7-dimethylamino group and is produced by a sequence involving aromatic nitration. Lymecycline is an example of an antibiotic developed by chemical modification of the primary amide function at C-2.

Having both amino and phenolic functions, tetracyclines are amphoteric compounds, and are more stable in acid than under alkaline conditions. They are thus suitable for oral administration, and are absorbed satisfactorily. However, because of the sequence of phenol and car-bonyl substituents in the structures, they act as chelators and complex with metal ions, especially calcium, aluminium, iron, and magnesium. Accordingly, they should not be administered with foods such as milk and dairy products (which have a high calcium content), aluminium-and magnesium-based antacid preparations, iron supplements, etc, otherwise erratic and unsatisfactory absorption will occur. A useful feature of doxycycline and minocycline is that their absorptions are much less affected by metal ions. Chelation of tetracyclines with calcium also precludes their use in children developing their adult teeth, and in pregnant women, since the tetracyclines become deposited in the growing teeth and bone. In children, this would cause unsightly and permanent staining of teeth with the chelated yellow tetracycline.

Although the tetracycline antibiotics have a broad spectrum of activity spanning Gramnegative and Gram-positive bacteria, their value has decreased as bacterial resistance has developed in pathogens such as Pneumococcus, Staphylococcus, Streptococcus, and E. coli. These organisms appear to have evolved mechanisms of resistance involving decreased cell permeability; a membrane-embedded transport protein exports the tetracycline out of the cell before it can exert its effect. Nevertheless, tetracyclines are the antibiotics of choice for infections caused by Chlamydia, Mycoplasma, Brucella, and Rickettsia, and are valuable in chronic bronchitis due to activity against Haemophilus influenzae. They are also used systemically to treat severe cases of acne, helping to reduce the frequency of lesions by their effect on skin flora. There is little significant difference in the antimicrobial properties of the various agents, except for minocycline, which has a broader spectrum of activity, and being active against Neisseria meningitidis is useful for prophylaxis of meningitis. The individual tetracyclines do have varying bioavailabilities, however, which may influence the choice of agent. Tetracycline and oxytetracycline are probably the most commonly prescribed agents. Tetracyclines are formulated for oral application or injection, as ear and eye drops, and for topical use on the skin. Doxycycline also finds use as a prophylactic against malaria in areas where there is widespread resistance to chloroquine and mefloquine (see page 363).

Their antimicrobial activity arises by inhibition of protein synthesis. This is achieved by interfering with the binding of aminoacyl-tRNA to acceptor sites on the ribosome by disrupting the codon-anticodon interaction (see page 407). Evidence points to a single strong binding site on the smaller 30S subunit of the ribosome. Although tetracyclines can also bind to mammalian ribosomes, there appears to be preferential penetration into bacterial cells, and there are few major side-effects from using these antibiotics.

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

R = NHOH, dactylocycline-A R = NO2, dactylocycline-B R = NHOAc, dactylocycline-C R = OH, dactylocycline-E

Figure 3.55

enzymes concerned allows many of the later steps to proceed even if one step, e.g. the chlorination, is not achievable. This has also proved valuable for production of some of the clinical tetracycline antibiotics.

One of the early intermediates in the pathway to chlortetracycline is 6-methylpretetramide (Figure 3.54). This arises from the poly-^-keto ester via an enzyme-bound anthrone (compare Figure 3.30). Reduction of one carbonyl will occur during chain extension, whilst the methylation must be a later modification. Hydroxylation in ring A followed by oxidation gives a quinone, the substrate for hydration at the A/B ring fusion. The product now features the keto tautomer in ring B, since its aromaticity has been destroyed. Chlorination of ring D at the nucleophilic site para to the phenol follows, and an amine group is then introduced stereospecif-ically into ring A by a transamination reaction. This amino function is then di-N-methylated using SAM as the methylating agent yielding anhydrochlorte-tracycline. In the last two steps, C-6 is hydroxylated via an O2-, NADPH-, and flavin-dependent oxyge-nase giving the enone dehydrochlortetracycline, and NADPH reduction of the C-5a/11a double bond generates chlortetracycline.

A number of anthracycline antibiotics*, e.g. doxorubicin (Figure 3.56) from Streptomyces peuceticus and daunorubicin from S. coeruleoru-bicus, have structurally similar tetracyclic skeletons and would appear to be related to the tetracyclines. There are similarities in that the molecules are essentially acetate derived, but for the anthracyclines the starter group is propionate rather than malonamide, and labelling studies have demonstrated a rather different folding of the poly-P-keto chain (Figure 3.56). As a result, the end-of-chain carboxyl is ultimately lost through decar-boxylation. This carboxyl is actually retained for a considerable portion of the pathway, and is even protected against decarboxylation by methylation to the ester, until no longer required. Most of the modifications which occur during the biosyn-thetic pathway are easily predictable. Thus, the anthraquinone portion is likely to be formed first, then the fourth ring can be elaborated by a aldol reaction (Figure 3.56). A feature of note in molecules such as doxorubicin and daunorubicin is the amino sugar L-daunosamine which originates from TDPglucose (thymidine diphosphoglucose; compare UDPglucose, page 29) and is introduced in the latter stages of the sequence. Hydroxylation of daunorubicin to doxorubicin is the very last step. Doxorubicin and daunorubicin are used as antitu-mour drugs rather than antimicrobial agents. They act primarily at the DNA level and so also have cytotoxic properties. Doxorubicin in particular is a highly successful and widely used antitumour agent, employed in the treatment of leukaemias, lymphomas, and a variety of solid tumours.

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