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!

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

• 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

Future of Chemotherapeutic Agents