2. Antibiotics- Introduction, History, Classification, Mechanism of action and SAR
- 1. Antibiotics Prepared by Dr. Girish Kashid Asst. Prof. Sanjivani College of Pharmaceutical Education & Research
- 2. Antibacterial agents which impair protein synthesis: Translation They inhibit protein synthesis by binding to ribosomes and inhibiting different stages of the translation process.
- 5. Stages at which antibacterial agents inhibit translation.
- 7. The 30S subunit binds messenger RNA (mRNA) and initiates protein synthesis. The 50S subunit combines with the 30S subunit- mRNA complex to form a ribosome, the binds aminoacyl transfer RNA (tRNA) and catalyses the building of the protein chain. The ribosomes of eukaryotic cells are bigger (80S), consisting of 60S and 40S subunits. They are sufficiently different in structure from prokaryotic ribosomes that it is possible for some drugs to distinguish between them.
- 8. 4. Aminoglycosides Streptomycin was isolated from the soil microorganis Streptomyces griseus in 1944. a carbohydrate structure which includes basic amine groups.
- 10. Streptomycin was the first effective agent used against tuberculosis.
- 11. The drug then crosses the cell membrane by an energy dependent process and is trapped inside the cell where it accumulates to relatively high concentrations. Binding to bacterial ribosomes now takes place to inhibit protein synthesis.
- 13. Neomycin is mostly used in a wide variety of local infection such as burns, ulcers, wounds, impetigo, infected dermatoses, furunculosis, conjunctivitis, etc. It is also employed as an adjuvant in topical steroid preparations to control secondary infections in the case of inflammatory disorders. furunculosis impetigo conjunctivitis,
- 15. It is effective against some Mycoplasma and gram- positive bacteria, for instance, Staphylococcus Pyogenes and Staphylococcus epidermidis. Along with penicillin it is found to be effective against Streptomyces fecalis. It is used invariably either alone or in combination with other drugs for a variety of disorders, namely : acute staphylococcal infections, gonorrhea, tuberculosis, acute urinary tract infections, for bowl sterilization in hepatic coma and also prior to bowl surgery.
- 16. Because the ribosomes in human cells are different in structure from those in bacterial cells, they have a much lower binding affinity for the aminoglycosides, which explains the selectivity of these drugs.
- 17. 5. Tetracyclines: The tetracyclines are bacteriostatic antibiotics which have a broad spectrum of activity. They are also capable of attacking the malarial parasite. The tetracyclines inhibit protein synthesis by binding to the 30S subunit of ribosomes and preventing aminoacyl-tRNA from binding. This stops the further addition of amino acids to the growing protein chain. Protein release is also inhibited.
- 18. General Structure of tetracyclines
- 20. General Chracteristics of the Tetracyclines (a) The tetracyclines are obtained by fermentation procedures from streptomyces species or by the chemical transformations of the natural products. (b) The important members of this family are essentially derivatives of an octahydronaphthacene, i.e., a hydrocarbon made up of a system of four-fused rings. Minocycline
- 21. (c) The tetracyclines are amphoteric compounds, i.e., forming salts with either acids or bases. In neutral solutions these substances exist mainly as Zwitter ions. (d) The acid salts of the tetracyclines that are formed through protonation of the dimethylamino group of C-4, usually exist as crystalline compounds which are found to be very much soluble in water. However, these amphoteric antibiotics will crystallize out of aqueous solutions of their salts unless they are duly stabilized by an excess of acid.
- 22. (e)The corresponding hydrochloride salts are used most commonly for oral administration and are usually encapsulated owing to their bitter taste. (f)The unusual structural features present in the tetracyclines afford three acidity constants (pKa values) in aqueous solutions of the acid salts. The thermodynamic pKa values has been extensively studied by Lesson et al.
- 24. The use of chlortetracycline has decreased over the years because it kills the intestinal flora that produce vitamin K. The tetracyclines can be divided into - 1. Shortlasting compounds, such as chlortetracycline, 2.Intermediate group of compounds which includes demeclocycline, 3.Longer-acting compounds which include doxycycline.
- 25. The tetracyclines were used originally for many types of respiratory infections, but have been largely replaced by β- lactams because of the problems of resistance. However, they are still the agents of choice for the treatment of Lyme disease (caused by bacteria of the Borrelia type which is spread by ticks), rickettsia, and infections caused by Chlamydia species.
- 26. They are also used to treat acne and a variety of different infections including respiratory and genital infections. Doxycycline has been found to be useful for the treatment and prophylaxis of malaria, and is cheaper than other antimalarial agents.
- 27. Structure Activity Relationship (SAR) 1. The amide function at C-2 is essential for activity. 2. Substitution at C-6 decreases chemical stability. e.g Oxytetracycline is chemically less stable than doxycycline. 3. In general, C-6 methylated analogs achieve higher blood levels. 4. The activity of 6-dimethyltetracycline (demecycline) and demeclocycline has established that the methyl function at C-6 may be replaced by hydrogen. 5.The activity of deoxycycline and 6-deoxy-6- demethyltetracycline (minocycline) shows that the presence of hydroxy moiety at C-6 is not essential either.
- 28. 6. Strong acid dehydrates tetracyclines utilising a 6-hydroxyl group and the 5-alpha hydrogen. This led to development of 6- deoxytetracyclins. 7. The 6-deoxy-6-methylenetetracyclines and their corresponding mercaptan adducts possess typical characteristics tetracycline activity and illustrate further the level of modification feasible at C-6 with the possible retention of biologic activity.
- 29. 8. C-7 substitution result in increased potency and the drug may sometimes be active against resistant microbial strains. 9. Electron withdrawing groups and electron donating groups both are equally effective at C-7, e.g.- chlortetracyclins contain an electron withdrawing group at C-7 and minocycline possesses an electron releasing group at C-7
- 30. 10. It is, however, interesting to observe that the subsequent removal of the 4-dimethylamino function affords a loss of about 75% of the antibiotic effect of the parent tetracyclines. 11. The X-ray diffraction studies reveal that the following stereochemical formula represents the orientations, as observed in the natural tetracyclines :
- 31. 12. X-ray diffraction studies further reveal that the 4- dimethylamino function is placed in a trans-orientation rather than the cis-form as inferred earlier by chemical investigations. It further establishes the presence of a conjugated system existing in the structures of tetracycline from C-10 through C-12.
- 32. 6. Macrolides: Macrolides are bacteriostatic agents. The best-known example of this class of compounds is erythromycin—a metabolite isolated in 1952 from the soil microorganism Streptomyces erythreus found in the Philippines, and one of the safest antibiotics in clinical use. The structure consists of a 14-membered macrocyclic lactone ring with a sugar and an amino sugar attached. The sugar residues are important for activity.
- 34. Erythromycin acts by binding to the 50S subunit of bacterial ribosomes to inhibit translocation. Erythromycin is unstable to stomach acids, but can be taken orally in a tablet form. The acid sensitivity of erythromycin is due to the presence of a ketone and two alcohol groups which are set up for the acid-catalysed intramolecular formation of a ketal.
- 35. One way of preventing this is to protect the hydroxyl groups. For example, Clarithromycin is a methoxy analogue of erythromycin which is more stable to gastric juices and has improved oral absorption.
- 36. Another method of increasing acid stability is to increase the size of the macrocycle to a 16-membered ring. Azithromycin contains a 15-membered macrocycle where an N -methyl group has been incorporated into the macrocycle. It is one of the world’s best-selling drugs.
- 38. 7. Lincosamides The lincosamide antibiotics have similar antibacterial properties to the macrolides and act in the same fashion. Lincomycin was the first of these agents and was isolated in 1962 from a soil organism called Streptomyces lincolnensis found near Lincoln, Nebraska. Chemical modification led to the clinically useful clindamycin with increased activity. Streptomyces lincolnensis
- 40. 9 Oxazolidinones The oxazolidinones are a new class of synthetic antibacterial agents discovered in recent years. They inhibit protein synthesis at a much earlier stage than previous agents, and, consequently, do not suffer the same resistance problems. Before protein synthesis can start, a 70S ribosome has to be formed by the combination of a 30S ribosome with a 50S ribosome.
- 41. The oxazolidinones bind to the 50S ribosome and prevent this from happening. As a result, translation cannot even start. Other agents that inhibit protein synthesis do so during the translation process itself. Linezolid was the first of this class of compounds to reach the market in 2000, and by 2010, it was netting sales of £716 million per year.
- 43. Other drugs which act on bacterial cell wall biosynthesis: 7. Polypeptide: β-Lactams are not the only antibacterial agents that inhibit cell wall biosynthesis. The antibacterial agents vancomycin, d-cycloserine and bacitracin also inhibit biosynthesis, though at different stages.
- 45. Vancomycin is a narrow-spectrum bactericidal glycopeptide produced by a microorganism called Streptomyces orientalis found in Borneo and India. It is active against Gram-positive cocci, particularly streptococci, staphylococci, and pneumococci. Vancomycin hydrochloride is always administered intravenously (never intramuscularly) Streptomyces orientalis
- 46. It is an amphoteric compound in which the presence of glucose, aspartic acid, N-methyl leucine, levulinic acid and 3- chloro -4-hydroxy- benzoic acid moieties has been recognised.
- 47. Vancomycin leucine aspartic acid levulinic acid 3- chloro -4-hydroxy- benzoic acid
- 49. ‘Capping’ of pentapeptide ‘tails’ by vancomycin.
- 50. The organism front which Johnson et. al. produced bacitracin in 1945 is a strain of Bacillus Subtilis. It is found to be a complex mixture of at least ten polypeptides (A, A', B, C, D, E, F1, F2, F3 and G) of which Bacitracin A fraction is believed to be most abundant and most potent. A divalent ion Zn++ enhances its activity. It is used as topical application. Bacitracin
- 51. Bacitracin is a mixture of related cyclic peptides produced by organisms of the licheniformis group of Bacillus subtilis. Bacitracin is primarily used as a topical preparation Bacillus licheniformis is a bacterium commonly found in the soil.
- 52. Bacitracin
- 53. Unclassified Chloramphenicol: Chloramphenicol was originally isolated from a microorganism called Streptomyces venezuela found in a field near Caracas, Venezuela. . Stereochemistry: It is now prepared synthetically and has two asymmetric centres. Only the R,R -isomer is active. Streptomyces venezuela Caracas
- 54. Mechanism of action: Chloramphenicol binds to the 50S subunit of ribosomes and appears to act by inhibiting the movement of ribosomes along mRNA, probably by inhibiting the peptidyl transferase reaction by which the peptide chain is extended.
- 55. Structural Features: The nitro group and both alcohol groups are involved in binding interactions. The dichloroacetamide group is also important, but can be replaced by other electronegative groups. Chloramphenicol is quite toxic and the nitro substituent is thought to be responsible for this. Chloramphenicol
- 56. Prepared by Dr. Girish Kashid 1. Wilson and Giswold’s Organic medicinal and Pharmaceutical Chemistry 2. Foye’s Principles of Medicinal Chemistry 3. Graham L. Patrick’s An Introduction to Medicinal Chemistry Seventh Edition 4. Medicinal Chemistry by Ashutosh Kar (Author) References
- 57. Prepared by Dr. Girish Kashid