Plants and Fungi Used to Treat Infectious Disease

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Plants and Fungi Used to Treat Infectious Disease
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Infectious Disease

• World wide, infectious disease is the number one
  cause of death accounting for approximately
  one-half of all deaths in tropical countries
• Infectious disease mortality rates are actually
  increasing in developed countries, such as US
• Infectious disease underlying cause of death in
  8 of deaths occurring in US

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Terms

• Antimicrobial a substance which destroys or
  inhibits the growth of microorganisms
• Antiseptic a substance that checks the growth
  or action of microorganisms especially in or on
  living tissue
• Antibiotic a substance produced by or derived
  from a microorganism and able to inhibit or kill
  another microorganism

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Overview

• Antibiotics from fungi
• Antimalarials from plants
• Other antimicrobials from plants

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Penicillin

• By-product of certain Penicillium species
• Inhibits the growth of gram-positive bacteria
• Blocks wall synthesis in bacteria and results in
  death of the bacterial cell by lysis
• Surpassed known therapeutic agents by suppressing
  bacterial growth without being toxic

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Discovery of Penicillin

• Folk treatments for wounds
• 19th Century observations of antibiosis by
  Penicillium spp
• Roberts - 1874
• Tyndall - 1881
• Others
• Flemming - 1928

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Sir Alexander Fleming
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Flemings Petri Dish - Penicillium notatum killed
the culture of Staphylococcus aureus
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Zone of Inhibition

• Around the fungal colony is a clear zone where no
  bacteria are growing
• Zone of inhibition due to the diffusion of a
  substance with antibiotic properties from the
  fungus

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Research continues

• In 1939, - Oxford University Howard Florey and
  Ernst Chain
• 1941 first human tests
• 1941 research moved to the US
• USDA labs in Peoria Illinois
• Summer 1943 Penicillium chrysogenum
• D-Day 1944
• 1945 Nobel Prize

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Start of Synthetics

• Soon after World War II, the pharmaceutical
  industry developed chemically altered versions of
  the penicillin molecule
• Modified penicillins provided for greater
  stability, broader anti-bacterial activity, and
  also oral administration which would permit home
  use of antibiotics

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Penicillin Today

• Still the most widely used antibiotic
• Still the drug of choice to treat many bacterial
  infections
• Scientists have continued to improve the yield of
  the drug
• Present day strains of P. chrysogenum are
  biochemical mutants that produce 10,000 times
  more penicillin than Fleming's original isolate

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Drawbacks

• Resistance - evolution of penicillin-resistant
  bacteria
• Allergies - Penicillin is the most frequent cause
  of anaphylaxis

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Synthesis of Penicillin

• Penicillin - one of a family of b-Lactam
  antibiotics
• b-Lactams produced by asexual fungi, some
  ascomycetes, and several actinomycete bacteria
• b-Lactams are synthesized from amino acids valine
  and cysteine

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b Lactam Basic Structure
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Penicillins

• When penicillin first isolated, it was found to
  be a mixture of various penicillins
• Different R groups attached to the molecule
• When large scale production began, it was found
  that by adding phenylacetic acid to the medium,
  the penicillin was all one type -penicillin-G

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Penicillin-G
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Penicillin-G

• Still an important antibiotic
• Disadvantage has been that it is unstable in acid
  conditions
• Given by injections - otherwise stomach acids
  would destroy

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Penicillin-V

• The addition of phenoxyacetic acid to the culture
  medium gives penicillin-V
• This is not as active as penicillin-G, but it is
  acid stable and can be given by mouth
• There are many other naturally occurring
  penicillins but these are still clinically very
  important

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Penicillin-V
phenoxy methyl penicillin
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Semi-Synthetic Penicillins

• A strain of Penicillium chrysogenum found that
  produced large amounts of 6-amino penicillanic
  acid (6-APA)
• 6-APA lacked antibiotic activity but it could be
  used to add a variety of side chains and create
  semi-synthetic penicillins
• methicillin and ampicillin
• Semi-synthetics have made penicillins a more
  versatile group of antibiotics

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RH
6-APA
Ampicillin
Methycillin
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Mode of Action

• b-lactam antibiotics inhibit formation of the
  bacterial cell wall by blocking cross-linking of
  the cell wall structure
• Bind to PBP penicillin binding proteins in cell
  membrane that function as transpeptidases
• Inhibit transpeptidases, which catalyze the final
  cross linking step in the synthesis of the
  peptidoglycan cell wall
• Result bacterial wall is weakened and cell
  bursts from osmotic pressure

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Resistance due to b-Lactamase
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Cephalosporin

• In 1948 Giuseppe Brotzu identified a compound
  produced by Cephalosporium acremonium that was an
  effective treatment for gram-positive infections
  as well as some gram-negative ones such as
  typhoid
• Brotzu sent a culture of this fungus to Florey.
  The team at Oxford once again isolated the active
  compound which they named cephalosporin
• Today a whole class of cephalosporins

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Cephalosporin
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Clinically Important Antibiotics