Aminoglycoside and Tetracyclines Antibiotics

Aminoglycoside and Tetracyclines Antibiotics

1. Dr. Aejaz Ahmed HOD & Associate Professor Department of Pharmaceutical Chemistry ALI-ALLANA COLLEGE OF PHARMACY, AKKALKUWA AMINOGLYCOSIDE ANTIBIOTICS Medicinal Chemistry –III UNIT-I

2. AMINOGLYCOSIDE ANTIBIOTICS The aminoglycoside antibiotics contain one or more amino sugars linked to an aminocytitol ring by glycosidic bonds. These are broad-spectrum antibiotics; in general, they have greater activity against gram-negative than gram-positive bacteria. The development of streptomycin, the first antibiotic of this group, was a well-planned work of Waksman (1944) and his associates, who isolated it from a strain of S treptomyces griseus. The aminoglycoside can produces severe adverse effects, which include nephrotoxity, ototoxicity, and neuro effects. These properties have limited the use of aminoglycoside chemotherapy to serious systemic indications. Some aminoglycosides can be administered for ophthalmic and topical purposes.

3. Examples of aminoglycoside antibiotics The organism that produces streptomycin, S. griseus, also produces several other antibiotic compounds: hydroxystreptomycin, mannisidostreptomycin, and cycloheximide. Among the many antibiotics isolated from that genus, several are compounds closely related in structure to streptomycin. Six of them— kanamycin , neomycin, paromomycin, gentamicin, tobramycin , and netilmicin — currently are marketed in the United States. Amikacin, a semisynthetic derivative of kanamycin A, has been added, and it is possible that additional aminoglycosides will be introduced in the future.

4. Mode of action of Aminoglycosides : The aminoglycosides exhibit bactericidal effects as a result of several phenomena. Ribosomal binding on 30s and 50s subunits as well as the interface produces misreading; this disturbs the normal protein synthesis. Cell membrane damage also plays an integral part in ensuring bacterial cell death. The binding of streptomycin and other aminoglycosides to ribosomes also causes misreading mutations of the genetic code, apparently resulting from failure of specific aminoacyl RNAs to recognize the proper codons on messenger RNA (mRNA) and hence incorporation of improper amino acids into the peptide chain.

5. Spectrum of Activity The aminoglycosides are classified as broad spectrum antibiotics, their greatest usefulness lies in the treatment of serious systemic infections caused by aerobic Gram-negative bacilli The choice of agent is generally between kanamycin, gentamicin, tobramycin , netilmicin , and amikacin. Aerobic Gram-negative and Gram-positive cocci (with the exception of staphylococci) tend to be less sensitive; thus, the beta- lactams and other antibiotics tend to be preferred for the treatment of infections caused by these organisms. Streptomycin is the most effective of the group for the chemotherapy of TB, brucellosis tularemia, and Yersinia infections. Paromomycin is used primarily in the chemotherapy of amebic dysentery Under certain circumstances, aminoglycoside and beta- lactam antibiotics exert a synergistic action in vivo against some bacterial strains when the two are administered jointly. Penicillin G and Streptomycin (or Gentamicin or Kanamycin) tend to be more effective than either agent alone in the treatment of enterococcal endocarditis.

6. Streptomycin and Dihydrostreptomycin Streptomycin sulphate is a white hygroscopic powder, very soluble in water, and practically insoluble in ethanol. The organism, S. griseus, releases the other substances, such as hydroxy streptomycin, mannisidostreptomycin, and cycloheximide, but do not reach up to the required activity/potency level. The development of resistant strains of bacteria and chronic toxicity constitutes major drawbacks of this category. It is an aminoglycoside antibacterial also used as an antitubercular drug. Properties and uses:

7. Gentamycins Properties and Uses: Gentamycin is a mixture of C1, C2, and C1A compounds, obtained commercially from Micromonospora purpurea . Gentamycin sulphate exists as white hygroscopic powder, soluble in water, and practically insoluble in alcohol, although it is a broad-spectrum antibiotic. It is used in the treatment of infections caused by gram-negative bacteria of particular interest and has a high degree of activity against P. aeruginosa , where the important causative factor is burned skin. It is used topically in the treatment of infected bed-sores, pyodermata , burns, and in the eye infection.

8. Netilmicin Sulfate Netilmicin sulfate, 1- N-ethylsisomicin ( Netromycin ), is a semisynthetic derivative prepared by reductive ethylation138 of sisomicin , an aminoglycoside antibiotic obtained from Micromonospora inyoensis.139 Structurally, sisomicin and netilmicin resemble gentamicin Cla, a component of the gentamicin complex.

9. Tobramycin The most important property of tobramycin is its activity against most strains of P. aeruginosa , exceeding that of gentamicin by twofold to fourfold. Some gentamicin -resistant strains of this troublesome organism are sensitive to tobramycin , but others are resistant to both antibiotics.137 Other Gram-negative bacilli and staphylococci are generally more sensitive to gentamicin . Tobramycin more closely resembles kanamycin B in structure (it is 3-deoxykanamycin B).

10. Structure–Activity Relationships Ring I is crucially important for characteristic Broad-spectrum antibacterial activity, and it is the primary target for bacterial inactivating enzymes. It is convenient to discuss sequentially aminoglycoside SARs in terms of substituents in rings I, II, and III. Few modifications of ring II (deoxystreptamine) functional groups are possible without appreciable loss of activity in most of the aminoglycosides. Ring III functional groups appear to be somewhat less sensitive to structural changes than those of either ring I or ring II. Although the 2-deoxygentamicins are significantly less active than their 2-hydroxyl counterparts, the 2-amino derivatives ( seldomycins ) are highly active. The 3-amino group of gentamicins may be primary or secondary with high antibacterial potency. Furthermore, the 4- hydroxyl group may be axial or equatorial with little change in potency.

11. Tetracycline:

12. Tetracycline's: - A broadest spectrum antibiotics. - The first of these compounds was Chlortetracycline followed by Oxytetracycline and tetracycline. The tetracyclines are obtained by fermentation procedures from Streptomyces spp. or by chemical transformations of the natural products.

13. Spectrum of Activity The tetracyclines have the broadest spectrum of activity of any known antibacterial agents. They are active against a wide range of Gram-positive and Gram-negative bacteria, spirochetes, mycoplasma, rickettsiae and chlamydiae. Their potential indications are, therefore, numerous. Because of incomplete absorption and their effectiveness against the natural bacterial flora of the intestine, tetracyclines may induce super infections caused by the pathogenic yeast Candida albicans.

14. Types of Tetracycline a) Naturally occurring : 1-tetracycline 2-chlortetracycline 3-oxytetracycline 4-demeclocycline

15. Semisynthetic occurring: 1-doxycycline 2-minocycline 3-meclocycline 4-lymecycline 5-methacycline 6-rolitetracyclin e

16. Structure and chemical characteristics

17. Structure Activity Relationship

18. R5 R4 R3 R2 R1. Chlortetracycline H H OH CH3 Cl Oxytetracycline H OH OH CH3 H Tetracycline H H OH CH3 H Demethyl chlortetracycline H H OR H CI Rolitetracycline + H OH CH3 H Metacycline H OH CH2 H Doxycycline H OH H CH3 H Minocycline H H H N(CH3) 2

19. Retention of the configuration of the asymmetric centres C-4, C-4a and C-12a is essential , whereas the configurations at C-5, C-5a and C-6 may be altered: 1- The amide hydrogen may be replaced with a methyl group, but larger groups have a deleterious effect except for those which are eliminated spontaneously in water .

20. 2-The dimethyl amino group may be replaced by a primary amino group without loss of in vitro activity but all other changes so far lead to decreased bacteriostatic action .

21. The hydrophobic part of the molecule from C-5 to C-9 may be altered in various ways: modifications at C-6 and C-7 in particular afford products having greater chemical stability. increased antibiotic activity and more favourable pharmacokinetics

22. Dehydrogenation to form a double bond between C-5a and C-11a markedly decreases activity Polar substituents at C-5 and C-6 contribute decreased lipid versus water solubility to the tetracycline

23. . The drugs are amphoteric , meaning they will form salts with both strong acids and bases. Thus, they may exist as salts of sodium or chloride.

24. Spectrum of Activity: -The tetracyclines are broad-spectrum antibiotics. -They are active against the following microorganisms: 1_ gram-positive and gram-negative bacteria 2_ spirochetes 3_ mycoplasmas , 4_ rickettsiae, 6_ Candida albicans

25. 7_ Mycoplasma pneumoniae 8_Chlamydia trachomatis 9_Borrelia recurrentis. 10_ Yersinia pestis 11_Vibrio cholerae 12_ Campylabacter fetus 13_Brucella specie 14_Streptococcus pneumoniee. 15_Neisserie gonorrhoeae

26. Mechanism of action:

27. Mechanism of resistance : There are three types of tetracycline resistance: 1) Tetracycline efflux. 2) Ribosomal protection. 3)Tetracycline modification.

28. Types of tetracyclines: 1-Demeclocycline:

29. Total Synthesis of the Tetracyclines :

30. Uses: -treat cancer patients with SIADH. -treat hyponatremia . -combined with hydrocortisone in a paste used by dentists . -treat trachoma.

31. Side effect: Dermatological: -Skin reactions, photosensitivity GIT :-nausea, vomiting, and diarrhea. CNS: -Dizziness,visualdisturbances . Immune System: -allergic reactions. Other: -yellowish-grayish-brown discoloration of the teeth.

32. Pharmacodynamics/Kinetics: -Absorption: ~50% to 80%. -Protein binding: 41% to 50% -Metabolism: Hepatic. -Half-life elimination: 10-17 hours -Time to peak, serum: 3-6 hours -Excretion: Urine

33. 2-Chlortetracycline : Uses: -used as antibacterial and antiprotozoal agent. -In veterinary medicine, it is commonly used to treat conjunctivitis in cats.

34. 3-Oxytetracycline : Uses: -treat Spirochaetal infection. -treating Non-Specific-Urethritis. -treating Clostridial wound infection and Anthrax.

35. Side effects: - Local irritation after intramuscular injection. - Gastrointestinal :-anorexia, nausea, vomiting. -Renal toxicity. - Hypersensitivity reactions :  Urticaria. - Blood :  Hemolytic anemia, thrombocytopenia, neutropenia

36. 1-tetracycline: Uses: -Tetracycline's primary use is for the treatment of acne vulgaris and rosacea . -It is also used to treat a very wide range of infections.

37. Side effects: -Gastrointestinal: anorexia, nausea, vomiting, diarrhea, -Skin: rashes, dermatitis. -Renal Toxicity -Hepatic Cholestasis : -Hypersensitivity Reactions: Anaphylaxis, Miscellaneous: Dizziness and headache

38. 4- Minocycline: Uses: -typhus fever and Q fever. -Psittacosis Trachoma -Nongonococcal urethritis. -Brucellosis.

39. Side effects: -Hypersensitivity reactions:Urticaria,anaphylaxis. -GI :Anorexia, nausea, vomiting, diarrhea. -Hepatic toxicity : Hyperbilirubinemia. -Respiratory:Cough, dyspnea. -Blood:Agranulocytosis, hemolytic anemia. -CNS: Convulsions, dizziness,sedation. -Oral cavity discoloration.

40. Pharmacokinetics : -rapidly absorbed from the GIT. -The peak plasma concentrations slightly decreased. -serum half-life ranged from 11 to 16 hours in hepatic dysfunction, and from 18 to 69 hours with renal dysfunction.

41. 5-doxycyclines Uses: used in the treatment of chronic adult periodontitis.

42. Side Effects: -Nausea, Vomiting,Diarrhea. -photosensitivity, rash. -dyspepsia -dysphagia. -Watery diarrhea -Bloody stools

43. Drug interaction of tetracyclines :: antacids containing aluminum, calcium, or magnesium, and iron-containing preparations Impaire the Absorption of tetracyclines anticoagulant therapy Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. bacteriostatic drugs interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin.

44. oral contraceptives Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. ergot alkaloids or their derivatives are given with tetracyclines. Increased risk of ergotism Bile acid sequestrants May decrease tetracycline absorption Iron preparations May decrease absorption of tetracyclines

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