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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
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
  • Death from infectious disease, ranked 5th in 1981, has become the 3rd leading cause of death in 1992
  • Infectious disease underlying cause of death in 8% of deaths occurring in US
terms
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
antibiotics vs antimicrobials
Antibiotics vs Antimicrobials
  • Antibiotics are toxic to microorganisms
  • Produced by fungi and/or bacteria
  • In the natural environment, antibiotics give the producing organism advantages over competing microorganisms for available nutrients and space
  • First antibiotic put into large-scale production was penicillin
antibiotics vs antimicrobials1
Antibiotics vs Antimicrobials
  • Antimicrobials produced by a variety of organisms including many plants
  • Plant-based antimicrobials provide protection for the plant against pathogenic bacteria or fungi
  • Plant-based antimicrobials represent a vast untapped source for medicines
  • Plants-based antimicrobials have enormous, but largely untapped, therapeutic potential for treating infectious disease
overview
Overview
  • Antibiotics from fungi
  • Antimalarials from plants
  • Other antimicrobials from plants
penicillin
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
Discovery of Penicillin
  • Infusions of moldy bread, cheese, meat, and soybeans have long history as folk treatment for wounds
  • 19th Century observations of antibiosis by Penicillium spp
    • Roberts - 1874
    • Tyndall - 1881
    • others
discovery of penicillin1
Discoveryof Penicillin
  • First discovered in 1928 by British physician Alexander Fleming
  • Accidental discovery of a contaminated bacterial culture
  • Fungus Penicillium notatum killed the culture of Staphylococcus aureus growing in the petri dish
zone of inhibition
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
additional work
Fleming carried out additional experiments, named it penicillin and published his findings

Fleming's paper attracted little attention at the time

Fleming’s experiments at purifying penicillin failed

It was 11 yrs before research advanced

Additional work
research at oxford university
Research at Oxford University
  • In 1939, Howard Florey and Ernst Chain began investigating naturally occurring antibacterial compounds and came across Fleming's report on penicillin
  • Within a year, the team at Oxford had chemically analyzed the compound and demonstrated that it could destroy certain types of bacteria in test tubes
progress continues
Progress Continues
  • War in Europe was escalating and Florey and Chain realized the potential for treating war wounds
  • Tests on infected animals were successful
  • 1941 the first human tests were conducted
  • Research was moved to various sites in the United States because of the war
  • Really miraculous cures were reported in human tests, and mass production was finally achieved
usda north regional research lab
USDA North Regional Research Lab
  • One team of researchers was looking for more high-yielding sources of penicillin
  • Moldy fruits and vegetables were routinely collected from local groceries stories
  • Fungi were isolated and tested for antibiotic production
summer of 1943
Summer of 1943
  • Cantaloupe was found contaminated with Penicillium chrysogenum.
  • The fungus produced 200 times more penicillin than Fleming's isolate.
  • This species was used in the industrial production of the drug and continues to be used today
mass production achieved
Mass Production Achieved
  • By D-Day in 1944, there was enough penicillin to treat all British and American casualties of the European invasion
  • By the time World War II ended, sufficient penicillin was available for civilian use
  • In 1945 Florey, Chain, and Fleming received the Nobel Prize for their work in developing the first "miracle" drug
start of synthetics
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
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 1 resistance
Drawbacks - 1: Resistance
  • Over-prescribing by physicians and veterinarians commonly occurs
  • Antibiotics were incorporated into animal feed for use in feedlots
  • Widespread use led to the evolution of penicillin-resistantbacteria
rise of resistant bacteria
Rise of Resistant Bacteria
  • Bacteria reproduce every 20 min
  • Time-table for the evolution of new strains faster than other organisms
  • By the early 1960s resistance was evident among many types of bacteria
  • By the early 1990s antibiotic resistance has become a major cause for concern among the medical community
drawback 2 allergies
Drawback-2: Allergies
  • Small percentage of population is allergic
  • Can result in severe or even fatal anaphylactic reactions
  • Penicillin is the most frequent cause of anaphylaxis
  • Several hundred die each year from anaphylaxis due to penicillin allergy
synthesis of penicillin
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
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 g1
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
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 v1
Penicillin-V

phenoxy methyl penicillin

semi synthetic penicillins
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 versatile group of antibiotics
slide33

R=H

6-APA

Ampicillin

Methycillin

mode of action
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 is bacterial wall is weakened and cell explodes from osmotic pressure
b lactamase
b-Lactamase
  • Within a decade of the introduction of penicillin, resistance was starting to develop
  • Resistance due to the presence of an enzyme that cleaved the b-lactam ring - enzyme called b-lactamase
  • By late 1950s looked like penicillin would dimish in importance
cephalosporin
Cephalosporin
  • In 1948 Giuseppe Brotzu, an Italian microbiologist 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.
cephalosporin group
Cephalosporin Group
  • Since its initial isolation, a whole group of cephalosporins have been manufactured.
  • Broader spectrum than penicillins
  • Effective against many penicillin-resistant strains of bacteria.
  • Much more expensive to produce; many of the newer cephalosporins are reserved for hospital use.
anti fungal compounds
Anti-Fungal Compounds
  • Antibiotics (per se) do not work on eukaryotic organisms or viruses
  • Need to control one eukaryote within the tissues of another eukaryote
  • There are several anti-fungal drugs that are widely used today but frequent side effects
  • The increase in fungal infections and the rise in antifungal drug resistance has led to the need for new drugs