Antimicrobial Chemotherapy

1
Anti-microbial Chemotherapy

• Chapter 13

2
Definitions

• Chemotherapeutic agents
• Anti-microbial agents
• Antibiotics
• Synthetic drugs
• Semi-synthetic drugs

3

• Antibiotics are easy to discover, but few are of
  value to us
• One study found 3 out of 400,000 useful
• Some have commercial uses other than treatment of
  disease
• Many are toxic to humans or just are not any
  better than what is currently available

4

• More than ½ of antibiotics in use come from
  bacteria
• Streptomyces (most)
• Bacillus
• Various molds - Penicillium and Cephalosporium
• Most are spore formers

5

• In 1910, Paul Ehrlich discovers synthetic drug
• Salvarsan
• In 1928, Alexander Flemming discovers 1st true
  antibiotic
• Penicillin
• In 1940, Howard Florey and Ernst Chain performed
  first clinical trials of penicillin
• Developed a method for mass production

6

• In 1935, Gerhard Dogmak discovers red dye which
  inhibits G bacteria
• In 1936, Ernest Fourneau discovered it was the
  sulfur portion of the dye that was active
• stimulated the mass production of sulfa drugs

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Selective Toxicity

• Magic bullet that causes damage to the
  microorganism without causing significant harm to
  the host
• Easier with prokaryotic pathogens
• Why?

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• Therapeutic dosage level
• eliminates pathogen
• Toxic dosage Level
• causes host damage
• Chemotherapeutic index
• maximum tolerable dose (per kg body weight) /
  minimum effective dose (per kg body weight)

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• Spectrum of activity refers to the range of
  different microorganisms against which the drug
  is effective.
• Broad-spectrum
• effective against a wide range of microbes
• May disturb normal microbiota
• allows overgrowth of competitors and
  opportunistic pathogens
• This is called a superinfection (also used to
  describe infection with antibiotic resistant
  organisms)

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• Narrow-spectrum
• effective against a narrow range of organisms or
  a single taxonomic group
• Anti-mycobacterials
• Synergism is an increased effect of two drugs
  when used together (e. g. clavulinic acid and
  amoxicillin).
• Antagonism is a reduction of a drugs desirable
  effect when administered with another (e.g.
  penicillin and tetracycline).

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Spectrum of Activity
12
Modes of Action
13
Inhibition of Cell Wall Synthesis

• Bacterial cell walls are composed of
  peptidoglycan
• Some anti-microbials prevent the synthesis of
  intact peptidoglycan
• Weakens cell wall and results in cell lysis
• Only actively growing cells are affected
• Human cells are unaffected WHY?

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Disruption of Cell Membrane

• May cause changes in the permeability of the
  plasma membrane
• Results in the loss of cell contents
• Some bind to phospholipids on the bacterial cell
  membrane
• Others bind to particular sterols in the cell
  membranes of fungi
• Why would these be ineffective on bacteria?
• They may prove toxic to the host cell, but animal
  cells usually have different sterols

15
Inhibition of Protein Synthesis

• Protein synthesis is a common feature of all
  cells
• Some anti-microbials target the ribosomes, which
  are different in prokaryotes (70S) and eukaryotes
  (80S)
• Mitochondria also have 70S ribosome there is the
  potential for damage to the host cell

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Inhibition of Nucleic Acid Synthesis

• May interfere with DNA replication or
  transcription
• Some have an extremely limited usefulness because
  they also interfere with mammalian DNA and RNA
• Others are widely used because they are more
  selectively toxic
• May act on specific bacterial enzymes

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Anti-metabolites

• Inhibition of the synthesis of essential
  metabolites
• particular enzymatic activity of microbes can be
  inhibited by a substance that closely resembles
  the normal substrate for the enzyme
• Sulfa drugs do this by substituting for PABA
  which is needed for the synthesis of folic acid
• The drug binds with the PABA enzyme and bacterial
  growth stops
• competitive inhibition

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PABA
Sulfa drug
PAS
Notice they have similar structures which allows
the sulfa drug or PAS to act as a competitive
inhibitor
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• Antibacterial drugs
• Inhibitors of cell wall synthesis
• Penicillin refers to a group of over 50 related
  antibiotics produced naturally or synthetically
• Prevent cross-linking of the peptidoglycan
• Natural penicillins are extracted from molds
• have a narrow range of activity
• Useful against gram bacteria and some
  spirochetes.
• Inactivated by the enzyme penicillase which is
  produced by many G - bacteria
• Semisynthetic penicillins
• developed to overcome the disadvantages of
  natural penicillins
• effective against some G- bacteria but not all
  are resistant to penicillinases

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Penicillinase cleaves the ßlactam ring from the
common nucleus of penicillin compounds Semi-synth
etic penicillins are synthesized by adding side
chains to the penicillin nucleus
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• Semi-synthetic Penicillins
• Penicilinase-resistant penicillins
• Methicillin resistance of Staph lead to
  discontinued use
• Extended-spectrum penicillins
• Ampicillin and amoxicillin
• Penicillins ?-lactamase inhibitors
• Combines penicillin with potassium clavulate
  which is a penicillinase non-competitive
  inhibitor

22

• Carbapenems - Polypeptide antibiotics that are
  also effective primarily against G bacteria
• Bacitracin
• named for bacillus isolated from a wound on a
  girl named Tracy
• Topical
• effective primarily against G bacteria
• Vancomycin Streptomyces
• toxicity was a problem initially but purification
  corrected problem
• narrow spectrum
• Considered last line of defense against
  Staphylococcus aureus infections
• Many strains are now resistant which is
  considered a medical emergency

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• Cephalosporins
• resemble penicillin
• broader spectrum
• resistant to penicillinases

24

• Anti-mycobacteriums
• effective against Mycobacterium which has a
  different cell wall structure than other bacteria
  
• Isoniazid (INH)
• Inhibits mycolic acid synthesis
• very effective against Mycobacterium tuberculosis
• Ethambutol
• Inhibits incorporation of mycolic acid
• only effective against mycobacteria