![1) Penicillins- Benzylpenicillin, Ampicillin
2) Cephalosporins- Cephalexin, Cephalothin
3) Aminoglycosides- Streptomycin, Kanamycin
4) Tetracyclines- Tetracycline, Chortetracycline
5) Macrolides- Erythromycin, Azithromycin
6) Lincomycins- Lincomycin, Clindamycin
7) Polypeptides- Vancomycin, Bacitracin
8) Miscellaneous- Chloramphenicol
9) Polyenes [Antifungal]- Amphotericin B, Nystatin.](https://image.slidesharecdn.com/antibacteralantibiotics2015-220705031022-237b2330/85/Antibacterial-Antibiotics-12-320.jpg)
![4 – thia – 1 – aza bicyclo [3.2.0] heptane
Stereochemistry – 3S : 5R : 6R
Penicillins](https://image.slidesharecdn.com/antibacteralantibiotics2015-220705031022-237b2330/85/Antibacterial-Antibiotics-15-320.jpg)
Antibacterial Antibiotics
- 1. Dr. A. S. Dhake Professor, SMBT College of Pharmacy, Dhamangaon, Nashik.
- 2. One organism destroys another to preserve itself. A substance is an antibiotic if – It is a metabolite or a synthetic analog of a naturally occurring antibiotic. It antagonizes the growth or survival of microorganisms. It is effective in low concentration.
- 3. Inhibition of cell metabolism Inhibition of cell wall synthesis Interaction with cell membrane Disruption of protein synthesis Inhibition of nucleic acid function
- 4. Site of Action Antibiotic Process Interrupted Type of Activity Cell Wall Penicillins Cell wall cross-linking Bactericidal Cephalosporins Cell wall cross-linking Bactericidal Vancomycin Mucopeptide Synthesis Bactericidal Bacitracin Mucopeptide Synthesis Bactericidal Cycloserine Syn. of cell wall peptides Bactericidal Cell membrane Amphotericin B Membrane Function Fungicidal Nystatin Membrane Function Fungicidal Polymyxins Membrane Integrity Bactericidal
- 5. Ribosomes Chloramphenicol Protein Synthesis B’static 50S subunit Erythromycin Protein Synthesis B’static Lincomycins Protein Synthesis B’static 30S Aminoglycosides Protein Synthesis and fidelity B’cidal Tetracyclines Protein Synthesis B’static Nucleic acids Actinomycin DNA & mRNA syns Pancidal Griseofulvin Cell division, Fungistatic microtubule assembly. Mitomycin C DNA synthesis Pancidal Rifampin mRNA synthesis B’cidal
- 6. 1) Drugs mainly effective against Gram+ve bacteria (A) For systemic infection – Penicillins, Lincomycin, macrolides, fusidic acid and vancomycin. (B) Used Topically – Bacitracin, novobiocin.
- 7. 2) Drugs mainly effective against Gram –ve bacteria. (A) For systemic infection – Aminoglycosides – streptomycin and gentamicin, polymyxins and cycloserine. (B) Used locally in the intestines – paromomycin.
- 8. 3) Drugs effective against both Gram+ve and Gram-ve bacteria: (A) Use for systemic infection – Broad spectrum penicillins –ampicillin, amoxicillin and Carbenicillin, cephalosporins and rifampicin. (B) Used topically – Neomycin, tyrothrycin, framycetin. 4) Drugs effective against Gram+ve and Gram-ve bacteria: rickettsia and Chlamydia - Tetracyclines, chloramphenicol.
- 9. 5) Drugs effective against acid fast bacilli: Rifampicin, streptomycin, capreomycin, viomycin, and cycloserine. 6) Drugs effective against protozoa: Paromomycin, tetracyclines, fumagillin. 7) Drugs effective against fungi: Nystatin, amphotericin B, griseofulvin, hamycin, pimaricin and saramycetin.
- 10. Source Drugs 1) Fungus: - Penicillins, griseofulvin, fumagillin. 2) Actinomycetes - Tetracyclines, chloramphenicol, ampicillin, erythromycin, Aminoglycosides. 3) Bacteria - Bacitracin, colistin, polymixin B, tyrothrycin. 4) Semi synthetic - Semisynthetic penicillins, cephalosporins, tetracyclines, dihydrostreptomycin. 5) Synthetic - Chloramphenicol, sulphonamides, isoniazid etc. Semi synthetic antibiotics are manufactured by chemical manipulation of microbial metabolites.
- 11. Bactericidal drugs are those which kill the bacteria and can be used when host defense mechanisms are inadequate. Bacteriostatic drugs stop the multiplication of the microbes and inhibit their growth. These can be used successfully only when the host defenses are unimpaired. 1) Primarily Bactericidal – Penicillins, cephalosporins, aminoglycosides and polymyxins. 2) Primarily Bacteriostatic – Tetracyclines, chloramphenicol, erythromycin, lincomycins and sulphonamides.
- 12. 1) Penicillins- Benzylpenicillin, Ampicillin 2) Cephalosporins- Cephalexin, Cephalothin 3) Aminoglycosides- Streptomycin, Kanamycin 4) Tetracyclines- Tetracycline, Chortetracycline 5) Macrolides- Erythromycin, Azithromycin 6) Lincomycins- Lincomycin, Clindamycin 7) Polypeptides- Vancomycin, Bacitracin 8) Miscellaneous- Chloramphenicol 9) Polyenes [Antifungal]- Amphotericin B, Nystatin.
- 13. 1) Penicillins. Discovered accidentally by Alexander Fleming in 1928. Isolation (1938) & first clinical trials (1941) carried out by Florey & Chain. MOA – Bactericidal, inhibit bacterial cell wall synthesis. Source – Fungus, Penicillium notatum (Now called P.chrysogenum).
- 15. 4 – thia – 1 – aza bicyclo [3.2.0] heptane Stereochemistry – 3S : 5R : 6R Penicillins
- 16. Penicillin G Benzylpenicillin R= Ph-CH2 Penicillin V Phenoxymethylpenicillin R= Ph-O-CH2- Repository Forms: - penicillin G procaine & penicillin G benzathine.
- 17. Properties of Penicillin G Active mainly against Gram+ve cocci & some Gram-ve cocci. Narrow spectrum of activity. Inactive orally due to degradation in stomach. Sensitive to β - lactamases.
- 18. SAR of Penicillins Strained β - lactam ring is essential. Free carboxylic acid is essential. Bicyclic system is important. Acylamino side chain is essential (Some exceptions) S is usual but not essential. Stereochem. is important.
- 19. Hypersentivity reactions – Anaphylaxis may occur on parentral adm, rash, eosinophilia etc. Other – GI distress, bone marrow suppression.
- 20. Many Staphylococcus aureus strains show resistance by producing penicillinase (β - lactamase). Such resistant strains can be treated by methicillin, nafcillin & the isoxazolyl penicillins – * cloxacillin, dicloxacillin & oxacillin. (* These 3 along with Penicillin V are acid resistant because R gr is e- withdrawing)
- 21. Ampicillin R Dα – aminobenzylpenicillin Ph – CH – NH2 Amoxicillin p – OH – Ph – CH – NH2
- 22. Properties Active against both Gram +ve & Gram –ve bacteria Acid resistant & therefore orally active Sensitive to penicillinase Absorption in g.i.t. is poor can be improved using prodrugs. Prodrugs of amp:- (bacampicillin, pivampicillin & talampicillin these are double esters or Acyloxymethylesters)
- 23. (Antipseudomonal penicillins) – Carboxypenicillins – carbenicillins, ticarcillin. Ureidopenicillins – mezlocillin, piperacillin. Besides the spectrum of ampicillin, these are active against Gram-ve Sp, Pseudomonas, Klebsiella, Enterobacter & Proteus.
- 24. β - lactam antibiotics, β - lactam ring fused with a dihydrothiazine ring. The first cephalosporin found was cephalosporin C (1948).
- 25. It has low potency, not absorbed orally but is non-toxic, more stable than Pen. G to acid and penicillinase, good ratio of Gram+ve/ Gram- ve activity. Thus, it serves as a lead compound. Cephalosporin C R = HOOC-CH(NH2)-(CH2)3-
- 26. SAR of cephalosporin C- β - lactam ring is essential Free carboxyl required at C-4. Bicyclic system is essential. Stereochemistry is important. Variations can be made in 7- acylamino side chain and 3- acetoxymethyl side chain. Semisynthetic approach through 7- amino cephalosporanic acid (7-ACA).
- 27. Cephalosporins Available- First generation- Cefazolin, cefadroxil, cephalexin,cephradine. Active against Gram+ve cocci and Gram-ve bacilli. Used to treat Klebsiella infections. Second generation- Cefoxitin, cefaclor, cefpodoxime, cefprozil. Extended Gram-ve coverage- H. influenzae. Used in UTI, gonococcal diseases Third generation- Ceftazidime, cefdinir, ceftibuten. Wider Gram –ve activity including Enterobacter, Serratia, Neisseria and Haemophilus. β -lactamase producing strains. Used in meningitis.
- 28. Fourth generation- Cefepime, cefpirome Highly resistant to β - lactamases. Used in UTI, pneumonia, greater activity against Gram+ve microorganism than 3rd generation. • 1st to 3rd generation- increased Gram-ve activity but lowered Gram+ve activity. Summary of properties – Injectable cephalosporins have high activity against many Gram+ve & Gram-ve bacteria. Cephalosporins have lower activity than penicillins but a better range. Most are poorly absorbed from g. i. t. Oral absorption is favoured by α – amino group on 7 – acyl substt. & uncharged group at C – 3 (eg. Me in cephalexin).
- 29. Newer β – lactam antibiotics – β – lactamase inhibitors – Clavulanic acid (1976) – Source – Streptomyces clavuligerus Used in combination with penicillins e.g. amoxicillin. Itself has weak antibiotic activity. Str. - β – lactam ring fused with oxazolidine ring, double bond in side chain – Z configuration.
- 30. Carbapenems – Imipenem (Thienamycin, 1976) – Source – Streptomyces cattleya Meropenem, ertapenem. β – lactam fused with 5- membered ring. Used in UTI, respiratory, abdominal & gynaecological infections.
- 31. (III) Aminoglycosides – Contain aminosugars MOA – Bactericidal, inhibit bacterial protein synthesis by binding to 30S ribosomal subunit. Streptomycin (1944) Source- Streptomyces griseus. Active against both Gram +ve and Gram –ve bacteria. Resistance, use restricted to plague, tularemia, brucellosis, bacterial endocarditis & tuberculosis.
- 32. Streptidine + streptose + N-methyl – L – Glucosamine Streptomycin Acid, H2O Streptidine + Streptobiosamine Amikacin (broadest spectrum aminoglycoside) Kanamycin, Gentamycin, tobramycin, neomycin, & netilmicin – active against many Gram –ve bacteria. Paromomycin – Broad spectrum antibacterial activity but use restricted to intestinal amebiasis. Mixture of two fractions paromomycin I & II
- 33. Neomycin – Source – Streptomyces fradiae Mixture of 3 compounds – Neomycin A (Neamine), B & C. Adverse Effects: Ototoxicity – vestibular & auditory damage. Nephrotoxicity – mild renal dysfunction. Neuromuscular blockade.
- 34. Broad spectrum agents obtained from Streptomyces Sp. Chlortetracycline discovered in 1948. MOA – Bacteriostatic, inhibit protein synthesis by binding to 30s ribosomal submit. Agents – Tetracycline, demeclocycline, oxytetracycline, doxycycline, minocycline.
- 35. Four linearly fused 6 - membered rings, parent str – naphthacene.
- 36. Stereochem is complex. Potentially chiral C – 4, 4a, 5, 5a, 6, 12a. Oxytetracycline and doxycycline have 5α – OH and 6 chiral centres. Others with non chiral C – 5, have 5 chiral centres.
- 37. Tetracyclines are amphoteric compounds – zwitterions in neutral solution. They show 3 pKa values in solution of acid salt. Acidic solutions undergo epimerization at C – 4 Epitetracyclines produced have low activity. Activity – Active against Gram-ve and Gram+ve organisms, mycoplasma, Chlamydia, rickettsia and some protozoa. Uses – Agents of choice in rickettsial, Chlamydial, , mycoplasmal infections, amebiasis and bacillary infections.
- 38. Adverse effects – GI distress. Hypersensitivity – skin rash, urticaria. Phototoxic reactions. Hepatotoxicity. Teeth discolouration. Interaction – Milk products, iron compounds, antacids & laxatives containing Ca, Mg, or Al reduce tetracycline absorption due to complexation.
- 39. (V) Chloramphenicol Source – Streptomyces venezeulae (1947). Now prepared by synthesis from p – nitroacetophenone. MOA – bacteriostatic ( primarily ). Inhibits protein synthesis by binding to 50s ribosomal submit. Activity – Broad spectrum. Active against many Gram+ve and Gram-ve organisms and rickettsia. Uses – Drug of choice against typhoid. Used in eye infections, rickettsial infections and infections resistant to penicillins.
- 40. Adverse effects – Bone marrow suppression and pancytopenia. Hypersensitivity – skin rash. Gray baby syndrome – in infants due to poor metabolism in liver.
- 41. 2 Chiral centres & 4 diastereomers. Only 1R, 2R – isomer or D – threo isomer is active. Taste – Bitter, given orally as capsules or insoluble palmitate ester.
- 42. VI) Macrolides Contain a large lactone ring (hence called macrolide), a ketone group and an amino sugar. Additional natural sugar may be present. Erythromycin (source – Streptomyces erythreus) & oleandomycin are widely used. Semi – syn. devt. of erythromycin – clarithromycin, azithromycin & dirithromycin. MOA – Bactericidal or bacteriostatic; inhibit protein synthesis by binding to 50S ribosomal subunit.
- 43. Activity Spectrum similar to penicillin (Gram +ve bacteria). Also against Mycoplasma, Chlamydia, Legionella. Uses Legionnaire’s disease, Mycolasma & chlamydial infections, diphtheria & pertussis.
- 47. • Wilson & Gisvold’s – Textbook of Organic, Medicinal And Pharmaceutical Chemistry, 2011 • Foye’s - Principles of Medicinal Chemistry, 2008 • Shargel L. et al - Comprehensive Pharmacy Review • Inamdar N.N - GPAT : A Companion (8th Edition) • Patrick G.L. – An introduction to Medicinal Chemistry Selected References :
- 48. Thank You