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
• 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
• 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
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 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
• 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
• 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 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
Sir Alexander Fleming
Fleming’s Petri Dish
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
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
• 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
• 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
• 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
• 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
• 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 - 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-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
• 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
• 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
b Lactam Basic Structure
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
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 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
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 is bacterial wall is weakened and cell
explodes from osmotic pressure
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
b-Lactamase
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
• 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.
Cephalosporin
Clinically Important Antibiotics
Site or mode of
Antibiotic Producer organism Activity action
Penicillin Penicillium chrysogenum Gram-positive bacteria Wall synthesis
Cephalosporin Cephalosporium acremonium Broad spectrum Wall synthesis
Griseofulvin Penicillium griseofulvum Dermatophytic fungi Microtubules
Bacitracin Bacillus subtilis Gram-positive bacteria Wall synthesis
Polymyxin B Bacillus polymyxa Gram-negative bacteria Cell membrane
Amphotericin B Streptomyces nodosus Fungi Cell membrane
Erythromycin Streptomyces erythreus Gram-positive bacteria Protein synthesis
Neomycin Streptomyces fradiae Broad spectrum Protein synthesis
Streptomycin Streptomyces griseus Gram-negative bacteria Protein synthesis
Tetracycline Streptomyces rimosus Broad spectrum Protein synthesis
Vancomycin Streptomyces orientalis Gram-positive bacteria Protein synthesis
Gentamicin Micromonospora purpurea Broad spectrum Protein synthesis
Rifamycin Streptomyces mediterranei Tuberculosis Protein synthesis
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