Antibiotics derived from the acetate metabolism

Transcription

1 Antibiotics derived from the acetate metabolism 1- Antibiotics with fused ring system: -Griseofulvin -Tetracyclines -[Fusidic acid] 2-Macrolide antibiotics 3-Polyene antibiotics

2 Griseofulvin: Produced by Penicillium spp (P. griseofulvum,.) 1 AcetylS-CoA + 6 MalonylS-CoA Polyketide Griseophenone C B A Dehydrogriseofulvin Griseofulvin Griseophenone C : Cl - deficiency: Griseooxanthrone C OH O OCH 3 A B C H 3 CO O OH Griseooxanthrone C Griseofulvin

3 Griseofulvin is antifungal medication used to treat a number of types of dermatophytoses(ringworm) This includes fungal infections of the nails and skin when antifungal creams have not worked. It is ineffective when applied topically. Available Dosage Forms: Tablet, Capsule and Suspension. it is well absorbed from the gut and selectively concentrated into keratin,(of the epidermis,nails and hair) so may be used orally to control dermatophytes such as Epidermophyton, Microsporium, and Trichophyton. Treatment for some conditions, e.g.(skin,hair, nails) - infections in fingernails, may have to be continued for everal months, but the drug is generally free of side-effecsts. -The antifungal action appears to be through disruption of the mitotic spindle, thus inhibiting fungal mitosis.

4 Tetracyclines Biosynthesized from 1 MalonamylCoA + 8 MalonylCoA (1NH 2 -CO-CH 2 -CO-SCoA +8 HOOC-CH 2 -CO-SCoA) C-19 Polyketide cyclisation C-6 methylation OH at C-4 dearomatization 4-keto derivative Cl - at C-7 amination and stepwise methylation at C-4 hydroxylation C-6 reduction of double bond in ring B Biosynthesized in Streptomyces spp. (S. aureofaciens, S. rimosus, ) Broad spectrum activity Protein synthesis inhibitor Side effects!

5 Tetracyclines 9 8 R 4 R 3 R R 1 NH(CH 3 ) 2 OH OH N H OH O OH O O R 5

6 Properties Of Tetracyclines 1- Having both amino and phenolic functions, tetracyclines are amphoteric compounds, and are more stable in acid than under alkaline conditions. 2-They are thus suitable for oral administration,and are absorbed satisfactorily. 3- Because of the sequence of phenol and carbonyl 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, otherwise erratic and unsatisfactory absorption will occur.

7 Properties Of Tetracyclines 4-Doxycycline and minocycline, their absorptions are much less affected by metal ions. 5*- 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 irreversible teeth damage and unsightly and permanent staining of teeth with the chelated yellow tetracycline(when antibiotica are given for children from 4 months until 6 years old). 6*-Hepatotoxicity and Kidneytoxicity (already) can be increase.

8 Medicinal uses -Tetracycline antibiotics have a broad spectrum of activity spanning Gram negative and Gram-positive bacteria. -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 2- They 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

9 Naturally occurring: Tetracycline, Chlorotetracycline, Oxytetracycline, Demeclocycline Semi-synthetic: Doxycycline, Meclocycline, Methacycline, Minocycline, Tigecycline,

10 Fusidic acid: is a steroidal antibiotic produced by cultures of the fungus Acremonium fusidioides -Protein synthesis inhibitor, -Fusidic acid is a bacteriostatic antibiotic that is often used topically in creams and eyedrops but may also be given systemically as tablets or injections. -Highly inhibitory: Staphylococci, corynebacteria, clostridia -Moderately inhibitory: tubercle bacilli, streptococci,.. Inactive: Coliform bacteria

11 Fusidic acid is a steroidal antibiotic produced by cultures of the fungus Acremonium fusidioides. -Fusidic acid and its salts are narrow-spectrum antibiotics active against Gram-positive bacteria -It is primarily used, as its sodium salt, in infections caused by penicillin-resistant Staphylococcus species, especially osteomyelitis since fusidic acid concentrates in bone. - It is usually administered in combination with another antibiotic to minimize development of resistance.

12 Macrolide antibiotics Synthesized from acetate units Produced by Streptomyces spp. Large lactone ring (12, 14, 16 or 17 atoms) Numerous CH 3 substituents in lactone ring 1-3 deoxy-sugar/sugar moieties attached to the ring Erythromycin A, B as examples Mainly active against Gram-positive bacteria and Mycoplasma spp.; useful in pat. with penicilline allergy Protein synthesis inhibitors SE: few, mainly GI symptoms

13 Erythromycin A: 1 [PropionylCoA] + 6 [2-MethylmalonylCoA] Polyketo-acid condensation Erythronolide ring (14 atoms) glycosidation Erytrhromycine (Azithromycine and Clarithromycin are semi-synthetic analog) -The antibiotic is a relatively safe drug with few seriousside-effects. Nausea and vomiting may occur, and if high doses are prescribed, a temporaryloss of hearing might be experienced [ 1 CH 3 -CH 2 -CO-SCoA + 6 HOOC-CH-(CH 3 )-CO-SCoA ]

14 Polyenes The group of antibiotics known collectively as polyenes is characterized by a large lactone ring (20 44 membered) containing a series of conjugated double bonds. -They are classified according to the longest conjugated chain present. -Medicinally important ones include the heptaene amphotericin B, and the tetraene nystatin. The macrolide ring is often linked via a hydroxyl group to an aminosugar unit The macrolide ring is probably derived from acetate and propionate. They are often mixtures of closely related compounds. Streptomyces are the usual producing organisms, and to date over 200 polyenes have been claimed Candida albicans is susceptible to the polyenes Cutaneous, intestinal and vaginal infections of Candida

15 Amphotericin B: formed of 16 acetate units ( 1 AcetylCoA + 15 MalonylCoA + 3 MethylmalonylCoA); macrolactone ring followed by glycosidation withd-mycosamine via OH at C-19 -Amphotericin B is active against most fungi and yeasts, but it is not absorbed from the gut so oral administration is restricted to the treatment of intestinal candidiasis -It is administered intravenously for treating potentially lifethreatening systemic fungal infections.

16 Nystatin A 1 Nystatin A 1 is too toxic for intravenous use, but has value for oral treatment of intestinal candidiasis, as lozenges for oral infections, and as creams for topical control of Candida species.

17 Antineoplastic anthracycline derivatives Produced by cultures of Streptomyces spp.; inhibit DNA dependent RNA synthesis SE: nausea, bone marrow depression, hair loss, local tissue necrosis; Biosynthesis: 1 PropionylCoA + 9 MalonylCoA Doxorubicin Epirubicin Daunorubicin Idarubicin

18 Doxorubicin is one of the most successful and widely used antitumour drugs. - Doxorubicin has one of the largest spectra of antitumour activity shown by antitumour drugs and is used to treat: acute leukaemias, lymphomas, and a variety of solid tumours. -Epirubicin the 4- epimer of doxorubicin, - It is particularly effective in the treatment of breast cancer, producing lower side-effects than doxorubicin. Daunorubicin is Similar to doxorubicin in its biological and chemical properties. - It is no longer used therapeutically to any extent. -It has a much less favourable therapeutic index than doxorubicin

19 -1It is a synthetic analogue of the anthracyclinones in which the non-aromatic ring and the aminosugar have both been replaced with aminoalkyl side-chains. This agent has reduced toxicity compared with doxorubicin, and is effective in the treatment of solid tumours and leukaemias.

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