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Plants and Fungi Used to Treat Infectious Disease. Infectious Disease. World wide, infectious disease is the number one cause of death accounting for approximately one-half of all deaths in tropical countries
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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
Terms • Antimicrobial = a substancewhich 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
Overview • Antibiotics from fungi • Antimalarials from plants • Other antimicrobials from plants
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
Discovery of Penicillin • Folk treatments for wounds • 19th Century observations of antibiosis by Penicillium spp • Roberts - 1874 • Tyndall - 1881 • Others • Flemming - 1928
Fleming’s Petri Dish - Penicillium notatum killed the culture of Staphylococcus aureus
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
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
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
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
Drawbacks • Resistance - evolution of penicillin-resistantbacteria • Allergies - Penicillin is the most frequent cause of anaphylaxis
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
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
Penicillin-G • Still an important antibiotic • Disadvantage has been that it is unstable in acid conditions • Given by injections - otherwise stomach acids would destroy
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
Penicillin-V phenoxy methyl penicillin
Semi-Synthetic Penicillins • A strain of Penicilliumchrysogenum 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
R=H 6-APA Ampicillin Methycillin
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
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