1. Antimicrobial Drugs

2. How were antimicrobial drugs first discovered?
Alexander Fleming
1928
S. aureus,
Penicillium notatum
Mass production: 1940s
Antibiosis
Lead to antibiotic
Different from chemotherapy!
It is estimated that another 300,000 soldiers would have died during WWII if penicillin had not been in mass production by that time.

3. Where do antibiotics come from?
From other bacteria found in
Soil
Bacteria
Streptomyces: more than half!
Bacillus
Molds
Penicillium
Cephalosporium

4. What is an antibiotic’s spectrum?
Number/types of organisms it affects
Narrow spectrum of antibiotic activity
Penicillin G: mostly only gram +
Broad spectrum antibiotic activity
Tetracycline
Pros vs cons
Lead to superinfections

5. How do antimicrobial drugs work?
Depends on the drug
Bactericidal or bacteristatic
Modes of action include
Cell wall destruction
Inhibiting transcription or translation
Plasma membrane damage
Inhibiting DNA synthesis
Inhibiting synthesis of metabolites

6. How can an antibiotic destroy the cell wall?
Penicillin and others
Prevent synthesis (crosslinking)
Cell then lyses due to weakened wall
Only affects actively growing cells
Does not affect humans

7. Can you discuss some examples?
Penicillin
Penicillin G
Narrow spectrum, penicillinase susceptible
Penicillinase-resistant penicillins
Methicillin
MRSA
Replacing methicillin: oxacillin, nafcillin
Extended spectrum penicillins
Ampicillin, amoxicillin
Effective against both gram + and –
Cephalosporins
Penicillinase resistant, gram – effective
Vancomycin
Narrow spectrum
Last resort

8. How can they inhibit protein synthesis?
Tetracyclines, chloramphenicol, streptomycin, etc.

9. How do they injure the PM?
Polypeptide antibiotics (e.g. polymyxin B)
Change permeability of PM

10. How do they inhibit DNA synthesis?
Limited usefulness… WHY?
Quinolones
Inhibits DNA gyrase
UTIs
Fluoroquinolones
Ciprofloxacin (Cipro)
Affects cartilage development
Can be used in adults

11. How do they inhibit synthesis of important metabolites?
Competitive inhibition
Synthetic drug
Sulfaniamide inhibits para-aminobenzoic acid (PABA)
PABA is precursor for making folic acid
Sulfa prevents conversion
Humans don’t make folic acid, we eat it!
Broad spectrum

12. What are some antifungal drugs?
Many target fungal sterols
Ergosterol vs. (humans) cholesterol
Azoles
Athlete’s foot, yeast infection treatment
Others target chitin cell wall
Echinocandins
Many others which we won’t worry about…

13. What about antiviral drugs?
Very few… WHY????
Drugs can attack
Attachment
Penetration
Uncoating
DNA/RNA synthesis
Virion assembly

14. Can you tell me about a couple?
Nucleosides and nucleotide analogs
Acyclovir: genital herpes
Interferons

15. What tests are used to identify antimicrobial activity?
Disk-diffusion
Can’t determine bactericidal vs. stasis
Gradient diffusion
Broth dilution
Can determine bactericidal vs. -stasis

16. 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

17. What’s next?

18. Is there a downside to antimicrobial or antibiotic use?
Yes!
Natural selection
Antibiotics
Always take the full prescription
They don’t work on viruses!

19. What types of resistance are there?
video
Destruction of the drug (e.g. penicillinase)
Prevention of drug penetration
Common with tetracycline
Alteration of drug target site
Rapid efflux
Heredity
Transformation, transduction, transposons

20. Resistance to Antibiotics

21. Future of Chemotherapeutic Agents
Antimicrobial peptides
Broad-spectrum antibiotics
Nisin (lactic acid bacteria)
Magainin (frogs)
Cecropin (moths)
Antisense agents
Complementary DNA that binds
a pathogen's virulence gene(s)
and prevents transcription
Fomivirsen to treat CMV retinitis
siRNA
Complementary RNA that binds mRNA to inhibit translation