1. Introduction
WHO; Tuberculosis in 2002, 2,000,000 death, 1/3 of the world’s population was infected.
1,900,000 children died worldwide of respiratory infections with 70% of these deaths in Africa and Asia.

2. History of antibacterial agents
Old age
Mouldy soybean curd in Chinese
Wine, myrrh, inorganic salts in Greek
Certain type of honey in Middle age.
Identification of bacteria : van Leeuwenhoek in 1670s
Fermentation by microorganism: Pasteur
Germ theory of disease : Lister
The reason of tuberculosis is microorganism, vaccination: Koch
The principle of chemotherapy; Ehrlich’s
Magic bullet, selective toxicity, chemotherapeutic index, therapeutic index.

4. Classification of bacteria : Appendix 5
Difference of bacterial and animal cells
- defined nucleus
Organelles
Biochemistry, e.g. vitamin synthesis
Cell wall, osmotic pressure, lysis

5. Five main mechanisms of antibacterial action
Inhibition of cell metabolism: sulphonamide
Inhibition of bacterial cell wall synthesis : penicillin, cephalosporins, cycloserine, vancomycin
Interactions with the plasma membrane: polymyxins, tyrothricin
Disruption of protein synthsis: rifamycins, streptomycin, tetracyclines, chloramphenicol
5. Inhibitions of nucleic acid transcription and replication: nalidixic acid, proflavin, quinolones, aminoacridines

6. SULPHONAMIDES
Titles modified

7. 1. Lead Compound Notes Prontosil - red dye
Antibacterial activity in vivo (1935)
Inactive in vitro
Metabolised to active sulphonamide
Acts as a prodrug
Sulphanilamide - first synthetic antibacterial agent acting on a wide range of infections
Arrow
Extended text boxes for prontosil and sulfanilamide

8. 2. Structure-Activity Relationships
Aromatic
para-Amino group
Sulphonamide
Primary amino group is essential (R1=H)
Amide groups (R1=acyl) are allowed
inactive in vitro, but active in vivo
act as prodrugs
Aromatic ring is essential
para-Substitution is essential
Sulphonamide group is essential
Sulphonamide nitrogen must be primary or secondary
R2 can be varied
Text modified
Amido to amide, para italics in diagram

9. 3. Prodrugs of sulfonamides
Enzyme
Notes
Amide group lowers the polarity of the sulphonamide
Amide cannot ionise
Alkyl group increases the hydrophobic character
Crosses the gut wall more easily
Metabolised by enzymes (e.g. peptidases) in vivo
Metabolism generates the primary amine
Primary amine ionises and can form ionic interactions
Ionised primary amine also acts as a strong HBD
Arrow modified
Shadow remoed from enzyme

10. 4. Sulphanilamide analogues
Notes
R2 is variable
Different aromatic and heteroaromatic rings are allowed
Affects plasma protein binding
Determines blood levels and lifetime of the drug
Affects solubility
Affects pharmacokinetics rather than pharmacodynamices

11. 5. Sulphanilamides - applications
Notes
Antibacterial drugs of choice prior to penicillins (1930s)
Superseded by penicillins
Current uses
Treatment of urinary tract infections
Eye lotions
Treatment of gut infections
Treatment of mucous membrane infections

12. 6. Mechanism of action para-Aminobenzoic acid
Dihydropteroate
para-Aminobenzoic acid
Dihydropteroate synthetase
Sulphonamides
Reversible
inhibition _
Dihydrofolate
L-Glutamic acid
Arrows and minuses
Dihydrofolate
reductase
NADPH
Tetrahydrofolate
(coenzyme F)
Trimethoprim _

13. 6. Mechanism of action Target enzyme
Dihydropteroate synthetase - bacterial enzyme
Not present in human cells
Important in the biosynthesis of the tetrahydrofolate cofactor
Cofactor is crucial to pyrimidine and DNA biosynthesis
Crucial to cell growth and division
Sulphonamides
Competitive enzyme inhibitors
Bacteriostatic agents
Not ideal for patients with weakened immune systems
Mimic the enzyme substrate - para-aminobenzoic acid (PABA)
Bind to the active site and block access to PABA
Reversible inhibition
Resistant strains produce more PABA
PABA added

14. 6. Mechanism of action Binding interactions Active site Active site O2 N O S N R H 2
Ionic bond
H-Bond
van der Waals
interactions

15. 6. Mechanism of action
Metabolic differences between bacterial and mammalian cells
Dihydropteroate synthetase is present only in bacterial cells
Transport protein for folic acid is only present in mammalian cells

16. 7. Sulphonamides - Drug Metabolism
Sulphathiazole
Insoluble metabolite
N-Acetylation
Notes
Sulphonamides are metabolised by N-acetylation
N-Acetylation increases hydrophobic character
Reduces aqueous solubility
May lead to toxic side effects
Arrow
S coloured

17. 8. Sulfonamides with reduced toxicity
Sulphathiazole
Sulphadiazine
Notes
Thiazole ring is replaced with a pyrimidine ring
Pyrimidine ring is more electron withdrawing
Sulphonamide NH proton is more acidic and ionisable
Sulphadiazine and its metabolite are more water soluble
Reduced toxicity
Silver sulphadiazine is used topically to prevent infection of burns
Electron withdrawing

18. 9. Examples of Sulphonamides
Sulphadoxine
Belongs to a new generation of sulphonamides
Long lasting antibacterial agent
Once weekly dosing regime
Sulphadoxine + pyrimethamine = Fanisdar
Used for the treatment of malaria
Pyrimethamine

19. 9. Examples of Sulphonamides
Succinyl sulphathiazole
Sulphathiazole
Succinic acid
Enzyme
Notes
Acts as a prodrug of sulphathiazole
Ionised in the slightly acidic conditions of the intestine
Too polar to cross the gut wall
Concentrated in the gut
Slowly hydrolysed by enzymes in the gut
Used versus gut infections
Arrow
Slightly acidic

20. 9. Examples of Sulphonamides
Benzoyl prodrugs
Benzoyl prodrug
Sulphonamide
Benzoic acid
Too hydrophobic to cross gut wall
Slowly hydrolysed by enzymes in gut
Used versus gut infections

21. 9. Examples of Sulphonamides
Sulphamethoxazole
Trimethoprim
Sulphamethoxazole + trimethoprim = co-trimoxazole
Agents inhibit different enzymes in same biosynthetic pathway
Strategy of sequential blocking
Allows lower, safer dose levels of each agent

22. 10. Sulphones Thought to inhibit dihydropteroate synthetase
Used in the treatment of leprosy