Antibiotics
• An antibiotic is a product
produced by a microorganism or a similar substance produced wholly or partially
by chemical synthesis, which in low concentrations, inhibits the growth of
other microorganisms.
• The term was first used by
Selman Waksman and derived from the word antibiosis means ”against life”
v Types of antibiotics:
1.
Natural: Produced by microorganisms,
mainly fungi and bacteria.
2.
Semi synthetic: Chemically modified
natural antibiotics.
3.
Synthetic: Completely synthesized in
the laboratory.
v
History of Antimicrobial
Drugs
– Paul
Ehrlich
• Coined the term
Chemotherapy
• 1909: Salvarsan for
Syphilis (Organoarsenic compound)
• Also known as
compound 606 and Arsphenamine.
• Magic Bullet
• He wanted to create
a chemical version of Behring”s antibodies.
• Basically working on
staining techniques in Koch’s group.
• After 605 attempts
at varying the dosage they still had no luck, compound 606 worked.
They nearly missed it! Only when Hata retested it.
a)
Prontosil (Sulfonamide)
• Gerhardt Domagk
(1932)
• Experimented with Dyes
to fight Blood Poisoning
• Some reasonable
success using mice
• His daughter
accidentally chased her Guinea Pig into his research room and infected herself
with some contaminated blood
• Domagk was forced to
try out his discovery and luckily it worked.
• The second chemical
bullet had been discovered
b)
Penicillin – The Guided
Missile
• Most infections caused by the powerful germs:
– Staphylococci
– Streptococci
• No drugs effectively
killed these germs
• Infections would spread
across the whole body
– Death likely
Alexander
Fleming’s Accidental Discovery
• In 1928, Fleming was
researching the Staphylococci germ.
• He had lots of Culture
plates lying around.
• He went on holidays with
his family.
• On his return and before
he cleaned up, he noticed that the Staphylococci on one of the plates had been
killed off.
• He immediately rushed to
see what was responsible.
• A small fungus called
Penicillium had blown through the window.
• He wrote a paper
explaining what had happened but he could not figure out a way of growing the
fungus.
Mass Production
of Penicillin
• Howard Florey and Ernst
Chain (1940)
– Read Fleming’s paper
with interest.
• World War II broke out in
1939
– Government grants to
discover a way of growing Penicillium.
• The Milk Bottle Process
– They needed as much
surface area as possible to grow the mould.
– Slowly gathered a
few grams of penicillin.
• Research was difficult in
war torn Britain
• Florey was sent to the USA
to continue his research
• December 1941 – US
Government invests $80 Million
• 4 Multi-National Drug
companies were told that the development of Penicillin was their top priority •
Huge factories were set up to mass production of fungus
• 1943 – Field Trials in
North Africa
• 1944 – Enough to supply
all the casualties on D-Day
• The Germans relied on the
inferior Sulphanomides for the duration of the war
Features of
Antimicrobial Drugs
·
Most modern antibiotics come from organisms living in the soil,
includes several bacterial and fungal species for e.g. Streptomyces, Bacillus,
Penicillium and Cephalosporium.
·
To commercially produce antibiotics
·
Strain is inoculated into broth medium.
·
Incubated until maximum antibiotic concentration is reached.
·
Drug is extracted from broth medium.
·
Antibiotic extensively purified.
·
In some cases drugs are chemically altered to impart new
characteristics. Semi-synthetic
i.
Selective toxicity
•
Antibiotics cause greater harm to microorganisms than to human
host
•
Generally by interfering with biological structures or biochemical
processes common to bacteria but not to humans
•
Toxicity of drug is expressed as therapeutic index
•
Lowest dose toxic to patient divided by dose typically used for
treatment
•
High therapeutic index = less toxic to patient
ii.
Antimicrobial action
•
Drugs may kill or inhibit bacterial growth
•
Inhibit = Bacteriostatic
•
Kill = Bacteriocidal
•
Bacteriostatic drugs rely on host immunity to eliminate pathogen.
•
Bacteriocidal drugs are useful in situations when host defenses
cannot be relied upon to control pathogen.
iii.
Spectrum of activity
•
Antimicrobials vary with respect to range of organisms controlled
iv.
Tissue distribution,
metabolism and excretion
•
Drugs differ in how they are distributed, metabolized and
excreted.
•
Important factor for consideration when prescribing
•
Rate of elimination of drug from body expressed in half-life
•
Time it takes for the body to eliminate one half the original dose
in serum
•
Half-life dictates frequency of dosage
•
Patients with liver or kidney damage tend to excrete drugs more
slowly
v.
Effects of combinations of
antimicrobial drugs
Combination some times used
to treat infections.
When action of one drug
enhances another, effect is synergistic.
When action of one drug
interferes with another, effect is antagonistic.
When effect of combination
is neither synergistic or antagonistic, effect said to be additive.
Adverse
effects
1.
Allergic reactions
Allergies to penicillin
2.
Toxic effects
Aplastic anemia -Body cannot
make RBC or WBC.
3.
Suppression of normal flora
Antibiotic associated
colitis
4.
Antimicrobial resistance
Inhibition of Cell wall Synthesis
Bacteria cell wall unique in
construction Contains Peptidoglycan Antimicrobials that interfere with the
synthesis of cell wall do not interfere with eukaryotic cell These drugs have
very high therapeutic index Low toxicity with high effectiveness Antimicrobials
of this class include β lactam drugs Vancomycin Bacitracin.
Disruption of Cell Membrane
Amphotericin B Binds to ergosterol of
fungal cell membrane, forming transmembrane channel leads to monovalent ion
leakage. Primary effect leading to fungal cell death.
Inhibition of protein
synthesis
Structure of prokaryotic
ribosome acts as target for many antimicrobials of this class Differences in
prokaryotic and eukaryotic ribosomes responsible for selective toxicity Drugs
of this class include Aminoglycosides, Tetracyclins, Macrolides
Chloramphenicol, Lincosamides, Oxazolidinones Streptogramins
Determination of Antimicrobial Susceptibility
• Susceptibility of organism
to specific antimicrobials is unpredictable.
• If serious infection,
several drugs are prescribed at one time with hope that one would be effective.
• Better approach is to
determine susceptibility.
• Prescribe drug that acts
against offending organism.
• Best to choose one that
affects as few others as possible.
a) Determining MIC
• MIC = Minimum Inhibitory
Concentration
• Quantitative test to
determine lowest concentration of specific antimicrobial drug needed to prevent
growth of specific organism.
• Determined by examining
strain’s ability to grow in broth containing different concentrations of test
drug.
b) Resistance to Antimicrobial Drugs
Mechanisms of
resistance
Drug inactivating enzymes-
Some organisms produce enzymes that chemically modify drug Penicillinase breaks
β-lactam ring of penicillin antibiotics
Alteration of target
molecule- Minor structural changes in antibiotic target can prevent binding.
c) Acquisition of resistance
• Can be due to spontaneous
mutation Alteration of existing genes Spontaneous mutation called vertical
evolution
• Or acquisition of new
genes Resistance acquired by transfer of new genes called horizontal transfer.
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