Chemotherapy

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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."

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Complexity of Antimicrobial Therapy
Antimicrobic Drug (antibiotic or synthetic drug)
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Complexity of Antimicrobial Therapy
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Complexity of Antimicrobial Therapy
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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

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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

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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

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Antibiotics Sources
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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

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Antibiotic Modes of Action
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Sites of Antibiotic Action
from http//teach.microbiol.unimelb.edu.au/micro/
interLab/sectionA/topic1/4.3.html
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Antibiotic Modes of Action
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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

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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

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Spectrum of Activity
Narrow Spectrum
Wide Spectrum
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Informed Best Guess
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Sensitivity Kirby-Bauer Method
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Tube Dilution Test
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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

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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

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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

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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
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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
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Various Antibiotics
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Antibiotic Modes of Action
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Cell-Wall Synthesis
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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

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

Augmentin
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Methicillin-Induced Lysis
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Antibiotic Modes of Action
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Generations of Cephalosporins
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Antibiotic Modes of Action
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Vancomycin
Vancomycin is employed particularly against
Methicillin-Resistant Staphylococci (MRS) plus
Streptococcus and Enterococcus
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Vancomycin
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Vancomycin
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Vancomycin
Before treatment
After treatment
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Antibiotic Modes of Action
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Quinolones
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Antibiotic Modes of Action
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Sulfanilimide
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Antibiotic Modes of Action
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Tetracycline
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Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
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Chloramphenicol
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Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
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Erythromycin (a Macrolide)
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Antibiotic Modes of Action
from http//project.bio.iastate.edu/Courses/MIPM3
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Aminoglycoside Antibiotics
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Blocking Ribosome Function
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Antibiotic Modes of Action
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Polymixin B
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Occurrence of Resistance
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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

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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

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Acquired Antibiotic Resistance
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Resistance in Simpler Terms
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?-Lactam Resistance
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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)

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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)

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Occurrence of Resistance
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Not Maintaining Course
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Rational for Combining Drugs
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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

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An Interesting Combination
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Quinolones
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Livestock (and plants) as Source of Resistance
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Some Antifungals
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Nucleotide Mimic Antivirals
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Complexity of Antimicrobial Therapy
Antimicrobic Drug (antibiotic or synthetic drug)
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Complexity of Antimicrobial Therapy
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Complexity of Antimicrobial Therapy
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Link to Next Presentation
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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