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Chemotherapy

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Title: Chemotherapy


1
Chemotherapy
  • Chemotherapy is the use of chemical substances
    (drugs) to treat disease
  • To be effective, a drug must combat the disease
    to a greater extent than that drug poisons the
    host (Selective Toxicity)
  • Symptoms of host poisoning we call side effects
  • An Antibiotic is "a chemical substance produced
    by microorganisms which has the capacity to
    inhibit the growth of bacteria and even destroy
    bacteria and other microorganisms in dilute
    solution."

2
Complexity of Antimicrobial Therapy
Antimicrobic Drug (antibiotic or synthetic drug)
3
Complexity of Antimicrobial Therapy
4
Complexity of Antimicrobial Therapy
5
Distinguishing Antibiotics
  • Antibiotics differ in terms of
  • their chemical structure
  • the organism they are or were isolated from
  • their site of action in bacterial cells
  • bacteriostasis versus bacteriostatic
  • the spectrum of bacteria they are active against
  • the degree to which susceptible organisms are
    capable of evolving resistance
  • toxicity to the host

6
Distinguishing Antibiotics
  • Antibiotics differ in terms of
  • their chemical structure
  • the organism they are or were isolated from
  • their site of action in bacterial cells
  • bacteriostasis versus bacteriostatic
  • the spectrum of bacteria they are active against
  • the degree to which susceptible organisms are
    capable of evolving resistance
  • toxicity to the host

7
Distinguishing Antibiotics
  • Antibiotics differ in terms of
  • their chemical structure
  • the organism they are or were isolated from
  • their site of action in bacterial cells
  • bacteriostasis versus bacteriostatic
  • the spectrum of bacteria they are active against
  • the degree to which susceptible organisms are
    capable of evolving resistance
  • toxicity to the host

8
Antibiotics Sources
9
Distinguishing Antibiotics
  • Antibiotics differ in terms of
  • their chemical structure
  • the organism they are or were isolated from
  • their site of action in bacterial cells
  • bacteriostasis versus bacteriostatic
  • the spectrum of bacteria they are active against
  • the degree to which susceptible organisms are
    capable of evolving resistance
  • toxicity to the host

10
Antibiotic Modes of Action
Skip to Next Page
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
11
Sites of Antibiotic Action
from http//teach.microbiol.unimelb.edu.au/micro/
interLab/sectionA/topic1/4.3.html
12
Antibiotic Modes of Action
13
Distinguishing Antibiotics
  • Antibiotics differ in terms of
  • their chemical structure
  • the organism they are or were isolated from
  • their site of action in bacterial cells
  • bacteriostasis versus bacteriostatic
  • the spectrum of bacteria they are active against
  • the degree to which susceptible organisms are
    capable of evolving resistance
  • toxicity to the host

14
Distinguishing Antibiotics
  • Antibiotics differ in terms of
  • their chemical structure
  • the organism they are or were isolated from
  • their site of action in bacterial cells
  • bacteriostasis versus bacteriostatic
  • the spectrum of bacteria they are active against
  • the degree to which susceptible organisms are
    capable of evolving resistance
  • toxicity to the host

15
Spectrum of Activity
Narrow Spectrum
Wide Spectrum
16
Informed Best Guess
17
Sensitivity Kirby-Bauer Method
18
Tube Dilution Test
19
Distinguishing Antibiotics
  • Antibiotics differ in terms of
  • their chemical structure
  • the organism they are or were isolated from
  • their site of action in bacterial cells
  • bacteriostasis versus bacteriostatic
  • the spectrum of bacteria they are active against
  • the degree to which susceptible organisms are
    capable of evolving resistance
  • toxicity to the host

20
Distinguishing Antibiotics
  • Antibiotics differ in terms of
  • their chemical structure
  • the organism they are or were isolated from
  • their site of action in bacterial cells
  • bacteriostasis versus bacteriostatic
  • the spectrum of bacteria they are active against
  • the degree to which susceptible organisms are
    capable of evolving resistance
  • toxicity to the host

21
Chemotherapeutic Index
  • It is realatively trivial to identify antibiotics
  • The trick is to identify antibiotics that are
    selectively toxicharming the pathogen but not
    the host
  • We employ a concept called the Chemotherapeutic
    Index as a measure of the degree of selective
    toxicity
  • The Chemotherapeutic Index is the ratio of the
    toxic dosage to the therapeutic dosage
  • The greater the ratio (or difference) of these
    two numbers, the easier it is to find a dosage
    that kills the pathogen without harming the host

22
Toxic-to-Therapeutic Ratio
Chemotherapeutic Index Toxic Dose/Therapeutic
Dose
Toxic
Small Ratio (dangerous)
Moderate Ratio
High Ratio (safe)
Drug Dosage (per Kg Body Weight)
Toxic
Therapeutic
Toxic
Therapeutic
Therapeutic
23
Finding Targets
Drug-Finding Ability as Function of Host-Pathogen
Similarity
Too Biochemically Similar as Fellow Eukaryotes
Bacteria
Too-Few Genes Share Host Metabolism
Fungi, Helminths, Protists
Number Drug Targets or Drugs with High
Chemotherapeutic Index
Different domain from Us!
Viruses, Cancer
Basically they are Us!
Biochemical Differences from Mammalian Host
24
Various Antibiotics
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
25
Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
26
Cell-Wall Synthesis
27
Penicillin Mechanism
Peptidoglycan from Staphylococcus aureus
?
?
  • D-Alanine is unusual amino acid since most are L
    optical isomer rather than D
  • The D-Ala-D-Ala repeat is the substrate of
    several so-called penicillin-binding proteins,
    which are enzymes involved in peptidoglycan
    synthesis

28
?-Lactam Antibiotics
Amoxycillin Ampicillin Aztreonam Carbapenem
(imipenem) Cephalosporin Methicillin

Augmentin
29
Methicillin-Induced Lysis
30
Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
31
Generations of Cephalosporins
32
Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
33
Vancomycin
Vancomycin is employed particularly against
Methicillin-Resistant Staphylococci (MRS) plus
Streptococcus and Enterococcus
34
Vancomycin
35
Vancomycin
36
Vancomycin
Before treatment
After treatment
37
Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
38
Quinolones
39
Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
40
Sulfanilimide
41
Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
42
Tetracycline
43
Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
44
Chloramphenicol
45
Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
46
Erythromycin (a Macrolide)
47
Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
48
Aminoglycoside Antibiotics
49
Blocking Ribosome Function
50
Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
02/302new/9_1chemother.html
51
Polymixin B
52
Occurrence of Resistance
53
Acquired Antibiotic Resistance
  • Three general mechanisms of acquisition of
    antibiotic resistance
  • Chromosomal mutation, which typically results in
    resistance due to a change in a target molecule
  • Acquisition of resistance plasmid, which
    typically results in resistance due to the
    acquisition of genes coding for proteins that
    manipulate the antibiotic, e.g., pumping of cell
    or chemically modifying
  • Acquisition or modification of genes via
    horizontal transfer of DNA snippet (I.e., via
    transformation or transduction)
  • Alternatively, a bacterium could be resistant to
    an antibiotic simply because it inherently lacks
    (or enters a stage that lacks evasion) either
    the antibiotic target molecule or lacks the means
    of allowing the antibiotic to reach its target

54
Acquired Antibiotic Resistance
  • Means of gaining resistance include
  • Gaining enzymes that destroy antibiotic molecules
  • Gaining proteins that modify the cell envelope,
    making it less permeable
  • Altering the target molecule that the antibiotic
    binds to (e.g., producing altered macrolecule,
    RNA or protein, or producing enzyme that either
    alters or fails to modify the target)
  • Gaining a protein that actively pumps the
    antibiotic out of the cell
  • Gaining an alternative target for the antibiotic,
    one that serves to mop up and otherwise reduce
    antibiotic concentrations within the cell
  • Note that mechanisms of resistance make bacteria
    less efficient
  • That is, there is usually a cost (e.g., in growth
    rate) associated with displaying antibiotic
    resistance

55
Acquired Antibiotic Resistance
56
Resistance in Simpler Terms
57
?-Lactam Resistance
58
Tetracycline Resistance
  • Chromosomal Resistance
  • Ribosome modification (I.e., via mutation in
    ribosome subunit encoding gene)
  • Extra-Chromosomal Resistance
  • Efflux of tetracycline (I.e., removal from cell
    faster than it enters)
  • Modification of tetracycline (I.e., destruction
    of translation-inhibiting structure)
  • Note that Tetracycline is Bacteriostatic rather
    than Bacteriocidal (and therefore tetracycline
    removal results in restoration of metabolism)

59
Polymixin B Resistance
  • Resistance to Polymixin B occurs due to mutations
    that reduce the negative charge of the outer
    membrane
  • Resistance occurs because Polymixin B is highly
    positively charged (lots of amino groups)

60
Occurrence of Resistance
61
Not Maintaining Course
62
Rational for Combining Drugs
63
Synergy vs. Antagonism
  • For antibiotics A and B used in combination
  • Actual killing rate A B multiplicative
    killing
  • Actual killing rate gt A B synergistic
    interaction
  • Actual killing rate lt A B antagonistic
    interaction
  • Typically bacteriostatic agents are antagonistic
    to bacteriocidal agents
  • Bacteriocidal agents, however, can have
    synergistic interactions
  • (think of the latter as one antibiotic weakens
    more bacteria than it kills, making the
    not-killed bacteria more susceptible to
    additional insult by the second antibiotic)
  • Multiplicative killing simply means that the
    two (or more) antibiotics do not affect, neither
    hindering nor helping, each others ability to
    kill

64
An Interesting Combination
65
Quinolones
66
Livestock (and plants) as Source of Resistance
67
Some Antifungals
68
Nucleotide Mimic Antivirals
69
Complexity of Antimicrobial Therapy
Antimicrobic Drug (antibiotic or synthetic drug)
70
Complexity of Antimicrobial Therapy
71
Complexity of Antimicrobial Therapy
72
(No Transcript)
73
Link to Next Presentation
74
Acknowledgements
http//project.bio.iastate.edu/Courses/MIPM302/302
new/9_1chemother.html http//www.medslides.com/mem
ber/Infectious_Diseases/antibiotic-resistance.ppt
http//www.sma.org.sg/whatsnew/convention2001/Sund
ay/WongSinYew.ppt
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