Antimicrobial Drugs
Antimicrobial Drugs
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Chemotherapy
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Antimicrobial drugs Interfere with
the growth of microbes within a host
Antibiotic
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The use of drugs to treat a disease
Substance produced by a microbe that, in
small amounts, inhibits another microbe
Selective toxicity
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A drug that kills harmful microbes without
damaging the host
Historical Perspective
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Treatment hopeless before 1935
Paul Ehrlich, early 20th century
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Father of chemotherapy
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Penicillin discovered -- gram positives
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Penicillin -- first therapeutic use
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Streptomycin -- gram negatives
Fleming -- 1929
Florey -- 1940
Waksman -- 1944
1947 -- Chloramphenicol -- broad spectrum
1947 - present -- many
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1928 – Fleming
discovered
penicillin,
produced by
Penicillium.
1940 – Howard
Florey and
Ernst Chain
performed first
clinical trials of
penicillin.
Figure 20.1
Properties of an ideal antibiotic
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broad spectrum
stable--long shelf life
soluble in body fluids
stable toxicity
Nonallergenic
reasonable cost
selectively toxic
not likely to induce bacterial resistance
Major genera that produce clinically
useful antibiotics
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Bacillus
Streptomyces
Cephalosporium
Penicillium
Major targets of antimicrobial activity
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Cell wall synthesis
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penicillins, cephalosporins (beta-lactamase producing
bacteria resistant to both, require active cell wall
synthesis in actively growing cultures), bacitracin
Cell membrane function
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amphotericin B (no growth requirement, changes membrane
permeability by binding to sterols in fungal membranes,
more side effects since membranes similar in all cells)
Protein synthesis
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Aminoglycides, tetracyclines, chloramphenicol
Major targets of antimicrobial activity
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DNA synthesisTranslation (mRNA--> protein):
 Transcription: rifampin (TB), actinomycin D
 Block movement of ribosome along mRNA: streptomycin,
tetracycline
 Prevent peptide bond formation by binding to ribosome:
chloramphenicol, erythromycin
Antimetabolites (structural analogs of natural substances
important in metabolism): PASA, sulfa drugs, INH
 PASA very similar in structure to PABA, required by bacteria
(but not human cells) for synthesis of folic acid
 When PASA is used in synthesis of folic acid, results in
nonfuctional folic acid analog and bacterial cell dies
Spectrum of Activity
The Action of Antimicrobial Drugs
The Action of Antimicrobial
Drugs
Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
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Penicillin
Natural penicillins
 Semisynthetic penicillins
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Penicilinase-resistant penicillins
 Extended-spectrum penicillins
 Penicillins + -lactamase inhibitors
 Carbapenems
 Monobactam
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Antibacterial Antibiotics
Inhibitors of Cell Wall Synthesis
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Cephalosporins
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2nd, 3rd, and 4th generations more effective against
gram-negatives
Polypeptide antibiotics
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Bacitracin
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Topical application
Against gram-positives
Vancomycin
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Glycopeptide
Important "last line" against antibiotic resistant S.
aureus
Antibacterial Antibiotics
Inhibitors of Protein Synthesis
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Chloramphenicol
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Broad spectrum
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Binds 50S subunit, inhibits peptide bond formation
Aminoglycosides
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Streptomycin, neomycin, gentamycin
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Broad spectrum
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Changes shape of 30S subunit
Antibacterial Antibiotics
Inhibitors of Protein Synthesis
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Tetracyclines
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Broad spectrum
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Macrolides
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Gram-positives
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Interferes with tRNA attachment
Binds 50S, prevents translocation
Erythromycin
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Gram-positives
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Binds 50S, prevents translocation
Disk-Diffusion Test
Figure 20.17
Definitions
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MIC
Minimal inhibitory
concentration
MBC
Minimal bactericidal
concentration
Broth Dilution Test
Figure 20.19
Antibiotic Resistance
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A variety of mutations can lead to
antibiotic resistance.
Mechanisms of antibiotic resistance
1. Enzymatic destruction of drug
2. Prevention of penetration of drug
3. Alteration of drug's target site
4. Rapid ejection of the drug
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Resistance genes are often on plasmids or
transposons that can be transferred
between bacteria.
Antibiotic Resistance
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Misuse of antibiotics selects for
resistance mutants. Misuse includes:
Using outdated, weakened antibiotics
 Using antibiotics for the common cold and
other inappropriate conditions
 Use of antibiotics in animal feed
 Failure to complete the prescribed regimen
 Using someone else's leftover prescription
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Figure 20.20
Effects of Combinations of
Drugs
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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.
Effects of Combinations of
Drugs
Figure 20.22
The Future of
Chemotherapeutic Agents
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Antimicrobial peptides
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Broad spectrum antibiotics from plants and
animals
Squalamine (sharks)
 Protegrin (pigs)
 Magainin (frogs)
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Antisense agents
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Complementary DNA or peptide nucleic acids
that binds to a pathogen's virulence gene(s)
and prevents transcription