Antibiotics are some of the most prescribed medicines today. They cover a large variety in terms of chemistry as well as therapeutic applications

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