1. Drugs, Microbes, Host – The Elements of Chemotherapy
Antibiotics - Still Miracle Drugs

2. Paul Ehrlich’s Magic Bullets
Salvarsan No. 606

3. Fleming and Penicillin

4. Antibiotics Topics - Antimicrobial Therapy - Selective Toxicity
- Survey of Antimicrobial Drugs
- Microbial Drug Resistance
- Drug and Host Interaction

7. Antibiotics Naturally occurring antimicrobials
Metabolic products of bacteria and fungi
Reduce competition for nutrients and space
Bacteria that produce them:
Streptomyces, Bacillus,
Molds
Penicillium, Cephalosporium

8. Selective Toxicity
Drugs that specifically target microbial processes, and not the human host cellular processes.

9. Selective Toxicity Mechanisms and sites
Mechanism of action
Bacterial cell wall
Nucleic acid synthesis
Protein synthesis
Cell membrane
Folic acid synthesis

11. Cell wall synthesis Bactericidal
Penicillin and cephalosporins – binds and blocks peptidases involved in cross-linking the glycan molecules
Vancomycin – hinders peptidoglycan elongation
Cycloserine – inhibits the formation of the basic peptidoglycan subunits

12. Antibiotics weaken the cell wall, and cause the cell to lyse.

13. The mechanism of action of penicillins and cephalosporins.

14. Penicillin Penicillin chrysogenum
A diverse group (1st, 2nd , 3rd generations)
Natural (penicillin G and V)
Semisynthetic (Ampicillin, Carbenicillin)
Structure
Thiazolidine ring
Beta-lactam ring
Variable side chain (R group)

15. Chemical structure of penicillins
The R group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive.

16. Penicillinase (b Lactamase)

17. Cephalosporin Cephalosporium acremonium (mold)
Widely administered today
Diverse group (natural and semisynthetic)
1st, 2nd, and 3rd generations
Structure
similar to penicillin except
Main ring is different
Two sites for R groups

18. The structure
of cephalosporins
The different R groups allow for versatility and improved effectiveness.

19. Inhibition of Protein synthesis
Aminoglycosides
Bind to the 30S ribosome
Causes Misreading of mRNA
Tetracyclines
Block attachment of tRNA
Chloramphenicol
Binds to the 50S ribosome
Prevents peptide bond formation

20. Inhibitors of Protein Synthesis
Broad spectrum, toxicity problems
Examples
Aminoglycosides: Streptomycin, neomycin, gentamycin
Tetracyclines
Macrolides: Erythromycin
Chloramphenicol

21. Aminoglycosides From Streptomyces Inhibit protein synthesis
Streptomyces synthesizes many different antibiotics such as aminoglycosides, tetracycline, chloramphenicol, and erythromycin.

22. Tetracycline Inhibits proteins synthesis Broad spectrum and low cost
Commonly used to treat sexually transmitted diseases
Minor side effect – gastrointestinal disruption

23. Erythromycin Inhibits protein synthesis Broad-spectrum
Commonly used as prophylactic drug prior to surgery
Side effects - low toxicity

24. Chloramphenicol Inhibits protein synthesis Broad-spectrum
Treat typhoid fever, brain abscesses
Rarely used now due to side effects – aplastic anemia

25. Aminoglycoside

26. Sites of inhibition on the procaryotic ribosome

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

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

29. Folic acid synthesis Sulfonamides (sulfa drug) and trimethoprim
Analogs
Competitive inhibition of enzymes
Prevents the metabolism of DNA, RNA, and amino acid

30. Sulfonamides compete with PABA for the active site on the enzyme.
The sulfonamide Sulfamethoxazole is commonly used in combination with trimethoprim

31. Antiviral Increasing types of drugs becoming available
However, it is difficult to maintain selective toxicity
Effective drugs – target viral replication cycle
Entry
Nucleic acid synthesis
Assembly/release
Interferon – genetically engineered antiviral protein from a human gene

32. Antiviral drug structures and their unique modes of action.

33. Antiviral drug structures and their unique modes of action.

34. Antiviral drug structures and their unique modes of action.

35. Other types of antimicrobials
Antifungal – ketoconizole
Antiprotozoan – metronidazole
Treat giardia
Antimalarial – Quinine
malaria
Antihelminthic – mebendazole
Tapeworms, roundworms

36. Mechanisms of Antibiotic Resistance
Enzymatic destruction of drug
Prevention of penetration of drug
Alteration of drug's target site
Rapid ejection of the drug

37. Antimicrobial Resistance
Relative or complete lack of effect of antimicrobial against a previously susceptible microbe

38. Antibiotic Resistance
Figure 20.20

39. Antibiotic Resistance
Intermicrobial transfer of plasmids containing resistance genes (R factors) occurs by conjugation, transformation,and transduction
Figure 20.20

40. What Factors Promote Antimicrobial Resistance?
Exposure to sub-optimal levels of antimicrobial
Inappropriate use
Exposure to microbes carrying resistance genes

41. Inappropriate Antimicrobial Use
Prescription not taken correctly
Antibiotics for viral infections
Antibiotics sold without
medical supervision
Spread of resistant microbes
in hospitals due to lack of hygiene

42. Inappropriate Antimicrobial Use
Inadequate surveillance or defective susceptibility assays
Poverty or war
Use of antibiotics in foods
Lack of quality control in manufacture or outdated antimicrobial

43. Antibiotics in Foods
Antibiotics are used in animal feeds and sprayed on plants to prevent infection and promote growth
Multi drug-resistant Salmonella typhi has been found in 4 states in 18 people who ate beef fed antibiotics

44. Antibiotic Drug and Host Interaction
Toxicity to organs
Allergic reactions
Suppress/alter microflora
Effective drugs

45. Tetracycline treatments can cause teeth discoloration.
Disrupting the normal flora in the intestine can result in superinfections.

46. Finding an effective drug for trreatment
Identify infectious agent
Perform sensitivity testing
Often the Minimum Inhibitory Concentration (MIC) is determined

47. The Kirby-Bauer Test.

48. Sensitivity test such as the Kirby-Bauer Test can be used to determine the effectiveness of a drug by measuring the zone of inhibition.

49. Consequences of Antimicrobial Resistance
Infections resistant to available antibiotics
Increased cost of treatment

50. Multi-Drug Resistant TB

51. Proposals to Combat Antimicrobial Resistance
Speed development of new antibiotics
Track resistance data nationwide
Restrict antimicrobial use
Direct observed dosing (TB)

52. Proposals to Combat Antimicrobial Resistance
Use more narrow spectrum antibiotics
Use antimicrobial cocktails

53. The Future of Chemotherapeutic Agents
Antimicrobial peptides
Broad spectrum antibiotics from plants and animals
Squalamine (sharks)
Protegrin (pigs)
Magainin (frogs)

54. The Future of Chemotherapeutic Agents
Antisense agents
Complementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcription