Antibacterials tetracyclines

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. 

Prolonged treatment with the classical antibacterial tetracyclines results in bacterial resistance and/or... 

Evidence is very limited but it has been suggested that all patients given long-term minocycline treatment should be well screened for the development of pigmentation, particularly if they are taking other drugs such as the oral contraceptives that are known to induce hyperpigmentation. Remember also that very rarely contraceptive failure has been associated with the use of minocycline and other tetracyclines, see Hormonal contraceptives + Antibacterials Tetracyclines , p.983. 

Some of the didanosine preparations (e.g. chewable tablets) are formulated with antacid buffers that are intended to facilitate didanosine absorption by minimising acid-induced hydrolysis in the stomach. These preparations can therefore alter the absorption of other drugs that are affected by antacids (e.g. azole antifungals, quinolone antibacterials, tetracyclines). This interaction may be minimised by separating administration by at least 2 hours. Alternatively, the enteric-coated preparation of didanosine (gastro-resistant capsules) may be used. 

Only 3 reports of pregnancies were identified in women who took metronidazole and an oral contraceptive (unspecified) in the adverse reactions register of the CSM in the UK for the years 1968 to 1984. A survey of oral contraceptive failure identified one failure due to metronidazole (48 of a total of209 cases were attributed to antibacterials), and a follow-up study identified one fiuther case. Another survey found one contraceptive failure in a woman taking metronidazole, but she was also taking dox-ycycline (see Hormonal contraceptives + Antibacterials Tetracyclines , p.983). It is possible that these cases represent chance associations. 

Note that doxycycline is increasingly used in the treatment of malaria. See Hormonal contraceptives + Antibacterials Tetracyclines , p.983, for further information on possible combined hormonal contraceptive failure with tetracyclines. 

The tetracycline molecule (1) presents a special challenge with regard to the study of stmcture—activity relationships. The difficulty has been to devise chemical pathways that preserve the BCD ring chromophore and its antibacterial properties. The labiUty of the 6-hydroxy group to acid and base degradation (12,13), plus the ease of epimerization (23) at position 4, contribute to chemical instabiUty under many reaction conditions. 

Under acidic conditions, dehydration to an anhydrotetracycline [20154-34-1] (8), C22H22N20y, occurs under basic ones, ring C opens to an isotetracycline [3811-31-2] (9), C22H24N20g. The anhydrotetracyclines, such as (8), appear to exhibit a mode of antibacterial action, but it is unlike that of tetracycline (24). Epimerization (23,25,26) at C-4 occurs in a variety of solvents within the pH range 2—6, particularly in acetic acid (25). A number of anions (27) facihtate this reaction. The reverse process, from 4-epitetracycline [79-85-6] C22H24N20g, to tetracycline, is promoted by chelation with ions such as calcium and magnesium (28). 

Conversion of the C-2 amide to a biologically inactive nitrile, which can be further taken via a Ritter reaction (29) to the corresponding alkylated amide, has been accomphshed. When the 6-hydroxyl derivatives are used, dehydration occurs at this step to give the anhydro amide. Substituting an A/-hydroxymethylimide for isobutylene in the Ritter reaction yields the acylaminomethyl derivative (30). Hydrolysis affords an aminomethyl compound. Numerous examples (31—35) have been reported of the conversion of a C-2 amide to active Mannich adducts which are extremely labile and easily undergo hydrolysis to the parent tetracycline. This reverse reaction probably accounts for the antibacterial activity of these tetracyclines. 

The hemiketal products (11) and (12) have been converted to the corresponding oximes, hydra2ones, and substituted amines (40,41). Although many of these derivatives exhibit substantial antibacterial activity, they are generally less active than the parent tetracyclines. 

The isolation of the 6-deoxytetracyclines (44) led to other chemical modifications of (1). 6P-Deoxytetracycline [5614-03-9] (13), prepared by catalytic hydrogenolysis of tetracycline (1), resulting ia an iaversion (45) of the configuration at the C-6 position, but retention of antibacterial activity. Catalytic reduction (7,8) of the 6-methylene derivative (14) yields both the 6a-methyl (15) and 6P-methyl compound (13). The 6a-isomer (15) is reported (7,45) to be more active than the 6P isomer (13). The a-isomer, doxycycline (6), is an example of a semisynthetic tetracycline that has become commercially useful. 

X-ray crystallographic studies (59) have defined the conformations and hydrogen bonding of the tetracyclines under nonpolar and polar conditions. These are shown ia Figure 3. It is beheved that the equiUbrium between the 2witterionic and nonioni2ed forms is of importance for the broad-spectmm antibacterial activity, membrane permeation, and pharmacokinetic properties. 

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. 

Resistance to Tetracyclines. The tetracyclines stiU provide inexpensive and effective treatment for several microbial infections, but the emergence of acquired resistance to this class of antibiotic has limited their clinical usehilness. Studies to define the molecular basis of resistance are underway so that derivatives having improved antibacterial spectra and less susceptibiUty to bacterial resistance may be developed. Tetracyclines are antibiotics of choice for relatively few human infections encountered in daily clinical practice (104), largely as a result of the emergence of acquired tetracycline-resistance among clinically important bacteria (88,105,106). Acquired resistance occurs when resistant strains emerge from previously sensitive bacterial populations by acquisition of resistance genes which usually reside in plasmids and/or transposons (88,106,107). Furthermore, resistance deterrninants contained in transposons spread to, and become estabUshed in, diverse bacterial species (106). 

The final sulphur-containing antibiotic proved be a highly active compound, superior in its antibacterial spectrum to all known tetracyclines. ... 

The broad antibacterial activity of rifaximin as well as its topical action make this antibiotic suitable for intrapocket administration in periodontal disease. As a matter of fact, local application of rifaximin compares well with tetracyclines and metronidazole in other extra-GI diseases, i.e. skin infections and BY, respectively (see above). On the other hand, rifampicin (rifampin), another rifamy-cin derivative, has been successfully used in the treatment... 

Tetracyclines, macrolides, and aminoglycosides are important classes of antibacterials... 

In the area of antibacterials, there are three important classes not yet mentioned. First, there are tetracyclines, the name reflecting their structural skeleton. Tetracycline itself... 

The discovery of a novel structural class of antibacterials is notable, as these are few and far between. The sulfa drugs, p-lactams, quinohnes, tetracyclines, macrohdes, and aminoglycosides have been around for decades. Multiple improvements have been made over time in each of these classes but without breaking out into new structural classes. There are two notable, recent examples of new stractural classes of antibacterials and these are worth knowing about. 

Other key classes of antibacterials include the tetracyclines (Aureomycin, Terramycin), macrolides (erythromycin, Zithromax, Biaxin), and aminoglycosides (streptomycin, amikacin, neomycin). These antibacterials are protein synthesis inhibitors. 

Tetracycline one of a class of antibacterials based on a tetracyclic skeleton and that act as a bacterial protein synthesis inhibitors. 

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