1. Antimicrobial Drugs
Fading Miracle?
BLS 206 Lecture
Hoza, A . S

2. Ehrlich’s Magic Bullets
• 1906: Paul
Ehrlich discovered
Salvarsan 606
• 1930s: sulfa drugs
discovered

3. Fleming and Penicillin

4. TERMINOLOGIES

5. Terminologies
Chemotherapy
• The use of drugs to treat a disease
• Selective toxicity:
– A drug that kills harmful microbes
without damaging the host

6. Terminologies
Antibacterial spectrum
Range of activity of an antibiotic
A broad spectrum
Antibiotic that can inhibit wide range of G- positive and G-
negative bacteria e.g. Carbapenems, 3-4th generation
cephalosporins, quinolones
A narrow spectrum
Antibiotic that is active only against a limited number of
bacteria e.g. penicillin G, 1-2nd generation cephalosporins,
oxazolidone

7. Bacteriostatic activity
Level of antimicrobial activity that inhibits the
growth of bacteria
Minimum inhibitory concentration (MIC)
The lowest concentration that inhibits the growth
of bacterial population
Bactericidal activity
Minimum bactericidal concentration (MBC)
The lowest concentration that kills 99.9% of
the bacterial population

8. Antibiotic combinations
Antibiotic synergism
Combination of antibiotics have enhanced activity
when tested together compared with each antibiotic
alone (e.g. 2 + 2 = 6)
e.g. ampicillin+gentamicin in entercoccal carditis
Additive effect
Combination of antibiotics has an additive effect
(e.g. 2 + 2 = 4)
e.g. combination of two ß-lactam antibiotics
Antibiotic antagonism
Combination in which the activity of one antibiotic
interferes with the activity of the other (e.g. 2 + 2 < 4)

9. Effects of Combinations of Drugs
• Synergism occurs when the effect of two drugs
together is greater than the effect of either alone.
• Antagonism occurs when the effect of two drugs
together is less than the effect of either alone.

10. Effects of Combinations of Drugs

11. Combined antibacterial therapy

12. Antibiotic/Antimicrobial
• Antibiotic:
– Chemical produced by a microorganism that
kills or inhibits the growth of another
microorganism
• Antimicrobial agent:
– Chemical that kills or inhibits the growth of
microorganisms

13. Antimicrobial Agents
• Disinfectant:
•antimicrobial agent used only on inanimate
objects
• Chemotherapeutic agent:
•antimicrobial agent that can be used internally
• Bactericidal:
•agent that kills bacteria
• Bacteriostatic:
•agent that inhibits the growth of bacteria

14. Microbial
Sources of
Antibiotics

15. Antibiotic Spectrum of Activity
• No antibiotic is effective against all microbes

16. Mechanisms of Antimicrobial Action
• Bacteria have their own enzymes for
– Cell wall formation
– Protein synthesis
– DNA replication
– RNA synthesis
– Synthesis of essential metabolites

17. Mechanisms of Antimicrobial Action
• Viruses use host enzymes inside host cells
• Fungi and protozoa have own eukaryotic enzymes
• The more similar the pathogen and host enzymes,
the more side effects the antimicrobials will have

18. Modes of Antimicrobial Action

19. Basic mechanisms of antibiotics

20. Basic mechanisms of antibiotic action
(1) Disruption of bacterial cell wall
 ß-lactam antibiotics
Penicillins, cephalosporins and cephamycins,
carbapenems and monobactams, ß-lactamase inhibitor/ß-
lactam combinations
Glycopeptides
 Vancomycin
Polypeptides
Bacitracin, polymyxins
Drugs used for treatment of mycobacterial infections
Isoniazid, ethinamide, ethambutol, cycloserine

21. Bacterial cell wall of G+ (A) and G- (B) bacteria

22. Gram-positive and Gram-negative bacteria

23. 2. Inhibition of protein synthesis
Acting at 30S ribosomes
Aminoglycosides
Tetracyclines
Acting at 50S ribosomes
Chloramphenicol
Macrolides
Clindamycin
Streptogramins
Oxazolidones

24. 3. Inhibition of nucleic acid synthesis
Acting on DNA replication
Quinolones
Metronidazole
Acting on RNA synthesis
Rifampin
Rifabutin

25. 4. Antimetabolites
Sulfonamides
Dapsone
Trimethoprim
Paraaminosalicylic acid

26. Antimicrobial Agents

27. Antimicrobial Agents

28. Antimicrobial Agents

29. Antibacterial Antibiotics Inhibitors of Cell Wall
Synthesis
• Penicillin (over 50 compounds)
– Share 4-sided ring (ß lactam ring)
• Natural penicillins
• Narrow range of action
• Susceptible to penicillinase (ß lactamase)

30. Prokaryotic Cell Walls
Gram positive cell Gram negative cell
wall wall

31. Penicillins
Figure 20.6

32. Penicillinase (b Lactamase)
Figure 20.8

33. Semisynthetic Penicillins
• Penicilinase- resistant penicillins
• Carbapenems: very broad spectrum
• Monobactam: Gram negative
• Extended- spectrum penicillins
• Penicillins + b-lactamase inhibitors

34. Other Inhibitors of Cell Wall Synthesis
• Cephalosporins
– 2nd, 3rd, and 4th
generations more
effective against
gram-negatives
Figure 20.9

35. Other Inhibitors of Cell Wall Synthesis
• Polypeptide antibiotics
– Bacitracin
• Topical application
• Against gram-positives
– Vancomycin
• Glycopeptide
• Important "last line" against antibiotic resistant
S. aureus

36. Other Inhibitors of Cell Wall Synthesis
• Antibiotics effective against
Mycobacteria:
– interfere with mycolic acid
synthesis or incorporation
– Isoniazid (INH)
– Ethambutol

37. Inhibitors of Protein Synthesis
• Broad spectrum, toxicity problems
• Examples
– Chloramphenicol (bone marrow)
– Aminoglycosides: Streptomycin, neomycin,
gentamycin (hearing, kidneys)
– Tetracyclines (Rickettsias & Chlamydia; GI tract)
– Macrolides: Erythromycin (gram +, used in
children)

38. Injury to the Plasma Membrane
• Polymyxin B (Gram negatives)
– Topical
– Combined with bacitracin and neomycin
(broad spectrum) in over-the-counter
preparation

39. Inhibitors of Nucleic Acid Synthesis
• Rifamycin
– Inhibits RNA synthesis
– Antituberculosis
• Quinolones and fluoroquinolones
– Ciprofloxacin
– Inhibits DNA gyrase
– Urinary tract infections

40. Competitive Inhibitors
– Sulfonamides (Sulfa drugs)
• Inhibit folic acid synthesis
• Broad spectrum
Figure 5.7

41. Antifungal Drugs
• Fungi are eukaryotes
• Have unique sterols in
their cell walls
• Pathogenic fungi are
often outside the body

42. Antiviral Drugs
• Viruses are composed of nucleic acid, protein
capsid, and host membrane containing virus proteins
• Viruses live inside host cells and use many host
enzymes
• Some viruses have unique enzymes for DNA/RNA
synthesis or protein cutting in virus assembly
Figure 20.16a

43. Antiviral Drugs
Nucleoside and Nucleotide Analogs
Figure 20.16a

44. Analogs Block DNA Synthesis
Figure 20.16b, c

45. Antiviral Drugs Enzyme Inhibitors
• Inhibit assembly
– Indinavir (HIV)
• Inhibit attachment
– Zanamivir (Influenza)
• Inhibit uncoating
– Amantadine (Influenza)

46. Antiviral Drugs Enzyme Inhibitors
• Interferons
– prevent spread of viruses to new cells (Viral
hepatitis)
• Natural products of the immune system in viral
infections

47. Antiprotozoan Drugs
• Protozoa are eukaryotic
cells
• Many drugs are
experimental and their
mode of action is unknown

48. Antihelminthic Drugs
• Helminths are
macroscopic
multicellular eukaryotic
organisms:
– tapeworms,
– roundworms,
– pinworms,
– hookworms

49. Antihelminthic Drugs
• Prevent ATP generation (Tapeworms)
• Alters membrane permeability (Flatworms)
• Neuromuscular block (Intestinal roundworms)
• Inhibits nutrient absorption (Intestinal roundworms)
• Paralyzes worm (Intestinal roundworms)

50. Measuring Antimicrobial Sensitivity
• E Test
• MIC: Minimal
inhibitory
concentration

51. Measuring Antimicrobial Sensitivity: Disk Diffusion

52. Penicillin