Antimicrobial Drugs

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.

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

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

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

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

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

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

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

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

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

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…

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

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

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

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

What’s next?

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

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

Resistance to Antibiotics

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