CHEM 100/100G

Chapter 2 – Penicillin /Assignment 2

Tutor：Maura

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 Part 1

Drugs, Drug Action, Drug Discovery and Drug Development

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 What is a drug?
• Drugs interact with the body to change its normal function. (acts
on a biological system to produce an effect)

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 How it works?
• Produces a predictable biological response via specific molecular
interactions with molecular components within a host cell or that of
an invading organism.

• Molecular level interaction targets: nucleic acids, proteins,

carbohydrates, lipids

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 Biomolecular Targets

• Proteins 蛋白质
• Includes enzymes, receptors, transporters, structural features and
hormones.

• Nucleic Acids 核酸
• DNA-anticancer drugs often target DNA
• RNA - protein expression

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 Biomolecular Targets

• Carbohydrates 碳水化合物
• cell surface recognition - interactions

• Lipids (fats) 脂肪
• major component of cell membranes, cholesterol transport, steroid
synthesis.

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 Past Paper

• List two classes of biomolecules that drugs interact with, in the

body. -Exam 2020

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 Drug Action

• Cells function by precise interactions between biomolecules, drugs

can be used to manipulate these interactions to restore the normal
healthy state.
• Drugs can work at cellular and organism(molecular) level

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 Animal and bacterial cells

• Differences between animal and bacterial cells can be exploited to

treat bacterial infections.
• Example: bacterial cells have cell wall while not in animal cells
no internal organelles in bacterial cells

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 Lead Compound

• Show a pharmaceutical effect in the drug discovery, but many may

require modification.

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Part 2
RELEVANT SCIENTIFIC DISCOVERIES PRE-PENICILLIN

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 Edward Anthony Jenner

• Jenner
• Father of Immunology
• Cowpox 牛痘 → Smallpox 天花

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 Louis Pasteur

• Pasteur
• Pasteurisation 巴氏杀菌 – heating food to slow microbial growth
• Proved “germ theory of fermentation”
• Used artificially weakened bacteria to create vaccines for anthrax
炭疽病, chicken cholera禽霍乱 and rabies狂犬病

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 Robert Koch

• Disproved “Miasma theory”: that disease was caused by “bad air”

rotting organic matter
• Demonstrated that Anthrax 炭疽病 is caused by Bacillus anthracis
and Tuberculosis 肺结核 by Mycobacterium tuberculosis.
• The Germ Theory of Disease: that disease is caused by
microorganisms
• Koch’s postulates
• Won Nobel Prize in 1905.

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• Edward Anthony Jenner，Louis Pasteur and Robert Koch – key
figures in demonstrating the link between microorganism and
diseases.

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 Joseph Lister

• Joseph Lister
• The pioneer of Antiseptic Surgery 消毒法手术 - which used
corrosive sprays on wounds and surgical instruments
• Used carbolic acid(now known as phenol) to clean wounds

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 William Henry Perkin
• Synthesis of mauvine
• enabled the science of organic chemistry to develop thus
ultimately facilitating the pharmaceutical industry

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 Paul Ehrlich
• The Father of Chemotherapy
• “Magic bullet theory”- An agent that will selectively kill disease
causing microbes without being toxic to human tissue.
• First using systematic analogue synthesis to develop
drug(salvarsan) and treat bacterial infection (Syphilis)

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 Past Paper
• Before the discovery of penicillin, there were a number of scientists who greatly
contributed to the development of medicinal chemistry and our understanding
of disease, including:
• Edward Jenner
• Louis Pasteur
• Robert Koch
• Joseph Lister
• William Perkin
• Paul Ehrlich
• Choose TWO of these scientists and briefly describe their contribution.
-Exam 2019，2020
• Briefly describe the contribution of one scientist to the development of medicinal
chemistry, prior to the discovery of penicillin. -Exam 2017

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 Definition
• Antibiotic- A drug that kills bacteria or inhibits bacterial growth
without significantly harming the host organism
• Prodrug- A compound that is not active itself, but is converted to
the active component after administration

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 The Sulfa Drugs(Sulfonamides)
• Bacteria make folic acid, humans do not
• Selectively target only bacteria and have no effect on humans.

• Prontosil mechanism-metabolism in body to form the active

compound sulfonamides, then sulfonamides used to mistake PABA
for bacteria in the process of synthesis of folic acid

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 The Sulfa Drugs(Sulfonamides)

• Develop Resistance (bacteria can adapt to use host folic acid)

• Allergic Reaction- resulted in their declined use.

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 Past Paper
• i) Prontosil is a prodrug. Give the definition of a prodrug.
• ii) Briefly describe the mechanism of action of prontosil. –Exam 20

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PART 3

The Discovery and War Time

Development of Penicillin

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 Alexander Fleming

• Alexander Fleming discovered penicillin in 1928 by accident, but

did not follow up as it was hard to produce.

• Published his results

• Initial attempts to extract, but chemical experiments demonstrated
that “penicillin” was very unstable and produced in only very small
amounts

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 Howard Florey and Ernst Chain

• Ernst Chain and Howard Florey revisited Penicillin in 1938 and

produced more pure penicillin which was promising in tests.

• Need to produce Penicillin in large quantities because of the war.

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 The War Time Development of Penicillin

• Florey sought help from the American pharmaceutical companies

• Florey group handed over freely the information about production,
extraction and purification of penicillin to the US pharmaceutical
companies as Florey considered patenting such information as
unethical
• Upscale of penicillin production carried out in America by Pfizer
during World War II, penicillin saves lives of many soldiers.
• Penicillin made available to civilians after the war.

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 Past Paper

• What was the major problem that needed to be overcome for penicillin to be
used to treat soldiers involved in World War II? -Exam 2017

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PART 4

The Science of Penicillin

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Penicillin structure

Bicyclic Ring system

essential

β-lactam
essential Carboxylic acid
must be "free"

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 Penicillin structure

• The chemical synthesis and structure determination of penicillin

was a difficult problem. 4-membered β-lactam structure which
was unknown at the time to occur in natural products, unstable
and proved very difficult to synthesize in the laboratory

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 Penicillin Mechanism (Cellular level)

• Penicillin inhibits the bacterial transpeptidase enzyme which

cross-links peptidoglycan strands in the bacterial cell wall. Without
these cross-links to produce the cell wall, the bacteria cannot
survive.
• Animal & bacterial cell difference-Human cells do not have cell
walls

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 Penicillin Mechanism (Molecular level)

transpeptidase enzyme in bacteria

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 Penicillin Mechanism (Molecular level)

• Penicillin irreversibly reacts with transpeptidase, no

transpeptidases are able to react with D-Ala, thus deactivated

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 Penicillin Mechanism (Molecular level)

Because the β-lactam ring of penicillin has a similar shape and

chemical structure to D-Ala-D-Ala, but due to the constrained ring,
penicillin is much more reactive.

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 Penicillin Resistance
• Decreased accumulation -reduced uptake
-increased efflux (pumps)
• Drug modification - β-lactamases produced
β-lactamase - secret by bacteria to destroy the β-lactam ring in
penicillin, thus makes penicillin inactive
- β-lactamase inhibitor (clavulanic acid)
- increase the size of R so that β-lactamase cannot reach the β-
lactam ring
• Altered target -alter Penicillin binding proteins
• Altered pathway -transpeptidases overproduced

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 6-APA

• 6-APA - Natural product -penicillin synthetic precursor

• The development of analogues was greatly assisted by the discovery of 6-APA
• Semi-synthesis- Analogues could be easily produced in just one synthetic transformation
on 6-APA instead of starting from scratch.

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 Past Paper

i) Describe the mechanism of action of penicillin with reference to the structure of D-Ala-
D-Ala. -Exam 20, 19, 18, 17, 16
Penicillin inhibits the bacteria transpeptidase in the cell wall, which responsible for the
production of cross-links. Bacteria can not survive with no cross-links in the cell wall. The
transpeptidase irreversibly react with penicillin instead of D-Ala-D-Ala, as the β-lactam ring of
penicillin has a similar shape and chemical structure to D-Ala-D-Ala. But due to the constrained
ring, penicillin is much more reactive

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 Past Paper

ii) One of the ways that bacteria try to become resistant to pencillins is by producing β-
lactamase enzymes. What does β-lactamase do to penicillins? -Exam 2020

β-lactamase - secret by bacteria to destroy the β-lactam ring in penicillin, thus makes
penicillin inactive

iii) State one thing that can be done to stop the effects of β-lactamase. -Exam 2020

- Take β-lactamase inhibitor with penicillin

- increase the size of R so that β-lactamase cannot reach the β-lactam ring

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 Past Paper
iv)Copy the structure of a general penicillin into your answer booklet and circle 3 of the
structural features essential for antibiotic activity. -Exam 2019, 2018, 2017,2016

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 Past Paper
v) Briefly explain why penicillins do not affect human cells. -Exam 2016, 18
Penicillin target on transpeptidase and cell wall, while human cell do not have cell wall.

vi) Briefly describe one type of adaptation by which bacteria become resistant to
penicillin. -Exam 2017
- Decreased accumulation
- Drug modification
- Altered target
- Altered pathway

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 Past Paper

β-lactamase inhibitor

i) By referencing the structure of the natural product 6-APA, explain why amoxycillin is
considered to be “semi-synthetic” -Exam 2019
Amoxycillin is produced in the synthetic transformation on the natural product 6-APA.

ii) Amoxycillin is often co-administered with clavulanic acid as a way to overcome penicillin
resistance. Explain how this works. -Exam 2019
clavulanic acid is administered to react with β-lactamase, which prevent β-lactamase from
reacting and destroying penicillin.
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PART 5

Other Classes of Antibiotics

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 Other Classes of Antibiotics

Other classes of antibiotics with different mechanisms of action are an ongoing

research effort.

Other classes of antibiotics include the glycopeptides, macrolides, aminoglycosides,

lipopeptides, tetracyclines, quinolones, oxazolidinones and antimicrobial peptides.

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 Past Paper
i) Name one other class of antibiotic. -Exam 2020,2019
glycopeptides, macrolides, aminoglycosides, lipopeptides, tetracyclines, quinolones,
oxazolidinones and antimicrobial peptides.

ii) Cephalosporins (pictured below) are another class of antibiotics. By referencing the
structure of the natural product 7-ACA, explain why cephalosporins are considered to
be “semi-synthetic” -Exam 2020

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 Assignment

• Define the term “drug”

• Briefly explain how drugs exert their effects (how drug works)

• Give two common types of drug targets

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 Assignment
• Give the name and chemical structure of the drug
Example 1-Paracetamol

include reference for figure

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 Assignment
• Give ONE of the overall biological effects of your chosen drug?
Pain relief
• What is the biomolecular target of this drug? Briefly explain how
the drug works.
- target on cyclooxygenase (protein)
- inhibit cyclooxygenase, and subsequently provide relief from the
symptoms of pain and inflammation.

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 Assignment
• Give one property of the “perfect drug” that your drug possesses and justify
your choice. If you are unable to answer question 7, give 2 properties for
question 8.
• Selective: A drug selective for its biological target minimizes side effects
making it safer to take.
• Favourable pharmacokinetics: what the body does to a drug
• Inexpensive
• Better activity than existing treatments
• Easy and efficient administration to the patient (oral often best although some
antibiotics formulated as “injection only” to prevent overuse)
• Good Therapeutic Index: Benefit at low dose vs harm at high dose.

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 Assignment
• Give one property of the “perfect drug” that your drug possesses and justify
your choice. If you are unable to answer question 7, give 2 properties for
question 8.
• Cheap - the wholesale price per dose in the developing countries is less than
US$0.01
• Easy and efficient administration - oral administration method, easy to operate.
Rectal and injectional administration methods are also available

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