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Drugs, Microbes, Host The Elements of Chemotherapy

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Title: Drugs, Microbes, Host The Elements of Chemotherapy


1
Drugs, Microbes, Host The Elements of
Chemotherapy
  • Antibiotics - Still Miracle Drugs

2
Paul Ehrlichs Magic Bullets
Salvarsan No. 606
3
Fleming and Penicillin
4
Antibiotics
  • Topics
  • - Antimicrobial Therapy
  • - Selective Toxicity
  • - Survey of Antimicrobial Drugs
  • - Microbial Drug Resistance
  • - Drug and Host Interaction

5
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6
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7
Antibiotics
  • Naturally occurring antimicrobials
  • Metabolic products of bacteria and fungi
  • Reduce competition for nutrients and space
  • Bacteria that produce them
  • Streptomyces, Bacillus,
  • Molds
  • Penicillium, Cephalosporium

8
Selective Toxicity
  • Drugs that specifically target microbial
    processes, and not the human host cellular
    processes.

9
Selective Toxicity Mechanisms and sites
  • Mechanism of action
  • Bacterial cell wall
  • Nucleic acid synthesis
  • Protein synthesis
  • Cell membrane
  • Folic acid synthesis

10
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11
Cell wall synthesis
  • Bactericidal
  • Penicillin and cephalosporins binds and blocks
    peptidases involved in cross-linking the glycan
    molecules
  • Vancomycin hinders peptidoglycan elongation
  • Cycloserine inhibits the formation of the basic
    peptidoglycan subunits

12
Antibiotics weaken the cell wall, and cause
the cell to lyse.
13
The mechanism of action of penicillins and
cephalosporins.
14
Penicillin
  • Penicillin chrysogenum
  • A diverse group (1st, 2nd , 3rd generations)
  • Natural (penicillin G and V)
  • Semisynthetic (Ampicillin, Carbenicillin)
  • Structure
  • Thiazolidine ring
  • Beta-lactam ring
  • Variable side chain (R group)

15
The R group is responsible for the activity of
the drug, and cleavage of the beta-lactam ring
will render the drug inactive.
Chemical structure of penicillins
16
Penicillinase (b Lactamase)
17
Cephalosporin
  • Cephalosporium acremonium (mold)
  • Widely administered today
  • Diverse group (natural and semisynthetic)
  • 1st, 2nd, and 3rd generations
  • Structure
  • similar to penicillin except
  • Main ring is different
  • Two sites for R groups

18
The different R groups allow for versatility and
improved effectiveness.
The structure of cephalosporins
19
Inhibition of Protein synthesis
  • Aminoglycosides
  • Bind to the 30S ribosome
  • Causes Misreading of mRNA
  • Tetracyclines
  • Block attachment of tRNA
  • Chloramphenicol
  • Binds to the 50S ribosome
  • Prevents peptide bond formation

20
Inhibitors of Protein Synthesis
  • Broad spectrum, toxicity problems
  • Examples
  • Aminoglycosides Streptomycin, neomycin,
    gentamycin
  • Tetracyclines
  • Macrolides Erythromycin
  • Chloramphenicol

21
Aminoglycosides
  • From Streptomyces
  • Inhibit protein synthesis

Streptomyces synthesizes many different
antibiotics such as aminoglycosides,
tetracycline, chloramphenicol, and erythromycin.
22
Tetracycline
  • Inhibits proteins synthesis
  • Broad spectrum and low cost
  • Commonly used to treat sexually transmitted
    diseases
  • Minor side effect gastrointestinal disruption

23
Erythromycin
  • Inhibits protein synthesis
  • Broad-spectrum
  • Commonly used as prophylactic drug prior to
    surgery
  • Side effects - low toxicity

24
Chloramphenicol
  • Inhibits protein synthesis
  • Broad-spectrum
  • Treat typhoid fever, brain abscesses
  • Rarely used now due to side effects aplastic
    anemia

25
Aminoglycoside
26
Sites of inhibition on the procaryotic ribosome
27
Injury to the Plasma Membrane
  • Polymyxin B (Gram negatives)
  • Topical
  • Combined with bacitracin and neomycin (broad
    spectrum) in over-the-counter preparation

28
Inhibitors of Nucleic Acid Synthesis
  • Rifamycin
  • Inhibits RNA synthesis
  • Antituberculosis
  • Quinolones and fluoroquinolones
  • Ciprofloxacin
  • Inhibits DNA gyrase
  • Urinary tract infections

29
Folic acid synthesis
  • Sulfonamides (sulfa drug) and trimethoprim
  • Analogs
  • Competitive inhibition of enzymes
  • Prevents the metabolism of DNA, RNA, and amino
    acid

30
Sulfonamides compete with PABA for the active
site on the enzyme.
The sulfonamide Sulfamethoxazole is commonly used
in combination with trimethoprim
31
Antiviral
  • Increasing types of drugs becoming available
  • However, it is difficult to maintain selective
    toxicity
  • Effective drugs target viral replication cycle
  • Entry
  • Nucleic acid synthesis
  • Assembly/release
  • Interferon genetically engineered antiviral
    protein from a human gene

32
Antiviral drug structures and their unique modes
of action.
33
Antiviral drug structures and their unique modes
of action.
34
Antiviral drug structures and their unique modes
of action.
35
Other types of antimicrobials
  • Antifungal ketoconizole
  • Antiprotozoan metronidazole
  • Treat giardia
  • Antimalarial Quinine
  • malaria
  • Antihelminthic mebendazole
  • Tapeworms, roundworms

36
Mechanisms of Antibiotic Resistance
  • Enzymatic destruction of drug
  • Prevention of penetration of drug
  • Alteration of drug's target site
  • Rapid ejection of the drug

37
Antimicrobial Resistance
  • Relative or complete lack of effect of
    antimicrobial against a previously susceptible
    microbe

38
Antibiotic Resistance
Figure 20.20
39
Antibiotic Resistance
Intermicrobial transfer of plasmids containing
resistance genes (R factors) occurs by
conjugation, transformation,and transduction
Figure 20.20
40
What Factors Promote Antimicrobial Resistance?
  • Exposure to sub-optimal levels of antimicrobial
  • Inappropriate use
  • Exposure to microbes carrying resistance genes

41
Inappropriate Antimicrobial Use
  • Prescription not taken correctly
  • Antibiotics for viral infections
  • Antibiotics sold without
  • medical supervision
  • Spread of resistant microbes
  • in hospitals due to lack of hygiene

42
Inappropriate Antimicrobial Use
  • Inadequate surveillance or defective
    susceptibility assays
  • Poverty or war
  • Use of antibiotics in foods
  • Lack of quality control in manufacture or
    outdated antimicrobial

43
Antibiotics in Foods
  • Antibiotics are used in animal feeds and sprayed
    on plants to prevent infection and promote growth
  • Multi drug-resistant Salmonella typhi has been
    found in 4 states in 18 people who ate beef fed
    antibiotics

44
Antibiotic Drug and Host Interaction
  • Toxicity to organs
  • Allergic reactions
  • Suppress/alter microflora
  • Effective drugs

45
Tetracycline treatments can cause teeth
discoloration.
Disrupting the normal flora in the intestine can
result in superinfections.
46
Finding an effective drug for trreatment
  • Identify infectious agent
  • Perform sensitivity testing
  • Often the Minimum Inhibitory Concentration (MIC)
    is determined

47
The Kirby-Bauer Test.
48
Sensitivity test such as the Kirby-Bauer Test can
be used to determine the effectiveness of a drug
by measuring the zone of inhibition.
49
Consequences of Antimicrobial Resistance
  • Infections resistant to available antibiotics
  • Increased cost of treatment

50
Multi-Drug Resistant TB
51
Proposals to Combat Antimicrobial Resistance
  • Speed development of new antibiotics
  • Track resistance data nationwide
  • Restrict antimicrobial use
  • Direct observed dosing (TB)

52
Proposals to Combat Antimicrobial Resistance
  • Use more narrow spectrum antibiotics
  • Use antimicrobial cocktails

53
The Future of Chemotherapeutic Agents
  • Antimicrobial peptides
  • Broad spectrum antibiotics from plants and
    animals
  • Squalamine (sharks)
  • Protegrin (pigs)
  • Magainin (frogs)

54
The Future of Chemotherapeutic Agents
  • Antisense agents
  • Complementary DNA or peptide nucleic acids that
    binds to a pathogen's virulence gene(s) and
    prevents transcription
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