1. Antimicrobial Drugs

2. Antimicrobial Drugs Chemicals used to treat microbial infections
Before antimicrobials, large number of people died from common illnesses
Now many illnesses easily treated with antimicrobials
However, many antimicrobial drugs are becoming less useful

3. Antimicrobial Drugs Chemotherapeutic agent= Antimicrobial drug=
Different types of antimicrobial drugs:
Antibacterial drugs
Antifungal drugs
Antiprotozoan drugs
Antihelminthic drugs

5. Paul Ehrlich
He observed that certain dyes stain bacterial cells and not animal cells
Theorized that there could be a dye or chemical that would harm bacterial cells but not human cells
Systematic search for chemical to cure syphilis
606th compound tested proved to be highly effective in treating laboratory animals

6. Gerhard Domagk
Discovered red dye, Prontosil effective in treating Streococcal infections in animals
No effect in test tubes
Enzymes in animals blood split Prontosil molecule into sulfanilamide- this acted against streptococcal
Sulfa Drug

7. Alexander Fleming Working on cultures of Staphylococcus
Contamination with mold
Noticed colonies growing near mold looked odd
Found that mold was secreting substance that was killing bacteria

8. Figure 20.1

9. Features of Antimicrobial Drugs
Most modern antibiotics come from species of microorganisms that live in the soil
To commercially produce antibiotic:
Select strain and grow in broth
When maximum antibiotic concentration reached, extract from medium
Purify
Chemical alter to make it more stable

10. Features of Antimicrobial Drugs: Selective Toxicity
Cause greater harm to microorganisms than to host
Chemotherapeutic index= lowest dose toxic to patient divided by dose typically used for therapy

11. Features of Antimicrobial Drugs: Antimicrobial Action
Bacteriostatic: inhibit growth of microorganisms
Bactericidal: Kill microorganisms

12. Features of Antimicrobial Drugs: Spectrum of Activity
Antimicrobial medications vary with respect to the range of microorganisms they kill or inhibit
Some kill only limited range : Narrow-spectrum antimicrobial
While others kill wide range of microorganisms: Broad-spectrum antimicrobial

14. Features of Antimicrobial Drugs: Effects of Combining Drugs
Combinations are sometimes used to fight infections
Synergistic: action of one drug enhances the activity of another
Antagonistic: activity of one drug interferes with the action of another

15. Features of Antimicrobial Drugs: Adverse Effects
Allergic Reactions: some people develop hypersensitivities to antimicrobials
Toxic Effects: some antimicrobials toxic at high concentrations or cause adverse effects
Suppression of normal flora: when normal flora killed, other pathogens may be able to grow to high numbers

16. Features of Antimicrobial Drugs: Resistance to Antimicrobials
Some microorganisms inherently resistant to effects of a particular drug
Other previously sensitive microorganisms can develop resistance through spontaneous mutations or acquisition of new genes

17. Mechanisms of action of Antibacterial Drugs
Inhibit cell wall synthesis
Inhibit protein synthesis
Inhibit nucleic acid synthesis
Injury to plasma membrane
Inhibit synthesis of essential metabolites

18. Figure 20.2

19. b-Lactam Drugs- inhibit cell wall synthesis
Irreversibly inhibit enzymes involved in the final steps of cell wall synthesis
These enzymes mediate formation of peptide bridges between adjacent stands of peptidoglycan
b-lactam ring similar in structure to normal substrate of enzyme
Drug binds to enzyme, competitively inhibit enzymatic activity

21. b-Lactam Drugs
Some bacteria produce b-lactamase- enzyme that breaks the critical b-lactam ring
b-lactam drugs include: penicillins and cephalosporins

22. Antibacterial medications that inhibit protein synthesis
Target ribosomes of bacteria
Aminoglycosides: bind to 30S subunit causing it to distort and malfunction; blocks initiation of translation
Tetracyclines: bind to 30S subunit blocking attachment of tRNA
Macrolides: bind 50S subunit and prevents continuation of protein synthesis

23. Figure 20.4b

24. Antibacterial medications that inhibit nucleic acid synthesis
Target enzymes required for nucleic acid synthesis
Fluoroquinolones: inhibit enzymes that maintain the supercoiling of closed circular DNA
Rifamycins: block prokaryotic RNA polymerase from initiating transcription

25. Antibacterial medications injure plasma membrane
Polymyxin B: binds to membrane of G- bacteria and alters permeability
This leads to leakage of cellular contents and cell death
These drugs also bind to eukaryotic cells to some extent, which limits their use to topical applications

26. Antibacterial drugs that inhibit synthesis of essential metabolites
Competitive inhibition by substance that resembles normal substrate of enzyme
Sulfa drugs

27. Antiviral Drugs Very few antiviral drugs approved for use in US
Effective against a very limited group of diseases
Targets for antiviral drugs are various points of viral reproduction

28. Nucleoside and Nucleotide analogs
Acyclovir- used to treat genital herpes
Cidofovir- used for treatment of cytomegaloviral infections of the eye
Lamivudine- used to treat Hepatitus B

31. Antiretrovirals Currently implies, a drug used to treat HIV
Tenofovir- nucleotide reverse transcriptase inhibitor
Zidovudine- nucleoside analog

32. Other enzyme inhibitors
Zanamivir (Relenza) and Oseltamivir phosphate (Tamiflu)- inhibitors of the enzyme neuominidase
Used to treat influenza
Indinavir- protease inhibitors

33. Interferons
Cells infected by a virus often produce interferon, which inhibits further spread of the infection
Alpha-interferon- drug for treatment of viral hepatitis infections

34. Antifungal drugs
More difficult to find point of selective toxicity in eukaryotes than in prokaryotes
Targets of antifungal drugs:
Agents affecting fungal sterols
Agents affecting fungal cell walls
Agents inhibiting nucleic acids

35. Agents affecting fungal sterols
Many antifungals target the sterols in the plasma membrane
Polyenes- used in systemic fungal infections, very toxic to kidneys
Azoles- used for athlete’s foot and vaginal yeast infections (miconizole)

36. Agents affecting fungal cell walls
primary target of selective toxicity is β-glucan
Inhibition of synthesis of this glucan results in an incomplete cell wall, and results in lysis of the cell
Caspofungin- first new class of antifungals in 40 years

37. Agents inhibiting nucleic acids
Flucytin- nucleotide analog of cytosine, interferes with the biosynthesis of RNA, and therefore protein synthesis

38. Antiprotozoan drugs Quinine still used to control malaria
Chloroquinone- synthetic derivative has largely replaced it
Mefloquinone- used in areas where resistance to chloroquinone has developed
Quinacrine- drug of choice for treating protozoan disease, giardiasis

39. Antihelminthic drugs
Praziquantel- used in treatment of tapeworms; kills worms by altering permeability of plasma membranes

40. Kirby-Bauer method for determining drug susceptibility
Bacteria spread on surface of agar plate
12 disks, each with different antimicrobial drug, placed on agar plate
Incubated- drugs diffuse outward and kill susceptible bacteria
Zone of inhibition around each disk
Compare size of zone to chart

41. Figure 21.10

42. Resistance to antimicrobial drugs
Drug resistance limits use of ALL known antimicrobials
Penicillin G: first introduced, only 3% of bacteria resistant
Now, over 90% are resistant

44. How do bacteria become resistant?
Spontaneous Mutation: happen as cells replicate
Gene Transfer: Usually spread through conjugative transfer of R plasmid

45. Slowing the emergence and spread of antimicrobial resistance
Responsibilities of Physicians: must work to identify microbe and prescribe suitable antimicrobials, must educate patients
Responsibilities of Patients: need to carefully follow instructions

46. Slowing the emergence and spread of antimicrobial resistance
3. Educate Public: must understand appropriateness and limitations of antibiotics ; antibiotics not effective against viruses 4. Global Impacts: organism that is resistant can quickly travel to another country - in some countries antibiotics available on non-prescription basis - antibiotics fed to animals can select for drug- resistant organisms

48. New Approaches to Antibiotic Therapy Are Needed
Scientists work to find new antibiotic targets in pathogens
Discovery of new and unique antibiotics is necessary