Transcript Nonspecific Immunity

Antimicrobial Drugs
How were antimicrobial drugs first discovered?
• Alexander Fleming
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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 paraaminobenzoic
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
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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