Chemotherapeutic Agents And an Antibiotic

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Chemotherapeutic Agents And an Antibiotic
A. Chemotherapy
Definitions
1. Chemotherapy = treatment of a disease by a chemical compound selectively directed against
invading microbes or abnormal cells.
The treatment of a disease with a chemical substance is known as chemotherapy. The chemical
substance is called a chemotherapeutic agent. Antibiotic is the discovery of a new and potent
class of antibacterial active chemotherapeutic agent. In general, naturally occurring substances
are distinguished from synthetic compounds by the name antibiotics. Some antibiotics are
prepared synthetically, but most of them are prepared commercially by microbial biosynthesis.
To be useful as a chemotherapeutic agent a substance must have selective toxicity for the
parasite, which means a low toxicity for host cells and high toxicity for the parasite. For this and
other reasons antiseptics, and germicides such as phenol are unsatisfactory as chemotherapeutic
agents. So, antibiotics are used as chemotherapeutic agents.
OR
Chemotherapy
Chemotherapy is the treatment of cancer by means of chemicals that kill cancer cells. These
“anti-cancer” drugs destroy cancer cells by stopping their growth and reproduction.
Unfortunately, normal healthy cells are also affected and this causes the well-known side effects
of chemotherapy. The normal healthy cells have an organized cell structure and repair
mechanisms in place. This results in them being able to reproduce new normal tissue after
chemotherapy.
Often, two or more drugs are given. This is called combination chemotherapy and forms the
basis of most of chemotherapy today. The rationale is that the different drugs enhance each
other’s effect and create a better effect combined than if they were used as single agents.

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Different chemotherapy drugs are chosen so that they do not have the same side effects on
tissue, in order for the side effects to be minimized.
The History of Chemotherapy
1. Paul Ehrlich developed the concept of chemotherapy to treat microbial diseases; he
predicted the development of chemotherapeutic agents, which would kill pathogens
without harming the host.
2. Sulfa drugs came into prominence in the late 1930s.
3. Alexander Fleming discovered the first antibiotic, penicillin, in 1929; its first clinical
trials were done in 1940.
Chemotherapy can have different goals:
 To cure cancer.
 To control the growth of cancer.
 To alleviate symptoms such as pain caused by cancer.
Chemotherapy can be used as a single treatment modality, but is also commonly used in
combination with surgery, radiotherapy and biological treatment in order to:
 Shrink a tumour before radiotherapy or surgery. This is called neo-adjuvant therapy.
 Destroy any remaining cancer cells after surgery or radiotherapy. This is called adjuvant
therapy.
 Enhance the effect of radiotherapy and biological therapy.
 Destroy recurring cancer or destroy cancer that has spread to other parts of the body.
How will your chemotherapy treatment plan be decided upon?
Each treatment plan is tailor-made to suit every individual and will depend on:
 He type of cancer.

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 The area of the body where the cancer is.
 The stage of the development of the cancer, eg. The size of the tumour in the affected
organ.
 Has there been any spread to the rest of the body?
 How the cancer influences the functioning of your body.
 Your general health.
 The purpose of the treatment, either curative or to relieve symptoms.
Administration of Chemotherapy
Chemotherapy can be given in different ways, namely: intravenous (into a vein), orally (in pill
form) or an injection under the skin or into muscle. In some cases it can be applied to the skin.
1) Intravenous administration
This is the most common method of administration. A thin needle is inserted into a vein on the
hand or lower arm. This needle is removed once the chemotherapy has been completed.
Chemotherapy can also be given intravenously by means of catheters, ports and pumps. A port is
a round plastic or metal chamber that is placed under the skin. It is connected via a thin tube to
one of the major vessels in the chest cavity. This method is more permanent and can be used for
as long as necessary.
2) Oral administration: The chemotherapy comes in pills, capsules, or liquids that you
swallow.
3) Topical: The chemotherapy comes in a cream that you rub onto your skin.
4) Injection: A needle and syringe deliver the chemotherapy drug either intramuscularly
(into a muscle) or subcutaneously (just below the skin).
5) Intra-arterial (IA): The chemotherapy goes directly into the artery that is feeding the
cancer.
6) Intraperitoneal (IP): The chemotherapy goes directly into the peritoneal cavity (the area
that contains organs such as your intestines, stomach, liver, and ovaries).

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Most patients receive chemotherapy as out-patients in the oncology unit and do not need to be
admitted to hospital. Sometimes, it may be necessary for hospital admission for certain
chemotherapy regimes.
Common Side Effects
Most people worry about whether they’ll have side effects from chemo, and, if so, what they’ll
be like. Here are some of the more common side effects caused by chemotherapy:
 Fatigue
 Hair loss
 Easy bruising and bleeding
 Infection
 Anemia (low red blood cell counts)
 Nausea and vomiting
 Appetite changes
 Constipation
 Diarrhea
 Mouth, tongue, and throat problems such as sores and pain with swallowing
 Nerve and muscle problems such as numbness, tingling, and pain
 Skin and nail changes such as dry skin and color change
 Urine and bladder changes and kidney problems
 Weight changes
 Chemo brain, which can affect concentration and focus
 Mood changes
 Changes in libido and sexual function
 Fertility problems
B. Antibiotics: Overview
Definitions
Definition: Antibiotics are molecules that kill, or stop the growth of, microorganisms, including
both bacteria and fungi.
 Antibiotics that kill bacteria are called "bactericidal"

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 Antibiotics that stop the growth of bacteria are called "bacteriostatic"
OR
Substance produced by a microorganism [or a similar product produced wholly (synthetic) or
partially (semi-synthetic) by chemical synthesis] that is capable, in low concentrations, of
inhibiting the growth of or killing other microoganisms.
Uses:
Antibiotics have been shown to be effective for many of the diseases of live stock. Antibiotic
medication through the feed represents a convenient and effective means of treating certain
specific disease conditions
Medical Uses:
Now a days physicians control approximately 50% of all maled^s and pathos.
The number of patients being rescued from surgery by antibiotic medicine is increasing
everyday.
Non-Medical Uses:
The application of antibiotics to animal was an outgrowth of the work in the human disease field.
Certain antibiotics have found widespread use as animal feed supplements to promote growth in
live stock. Additionally, antibiotics had some use in food preservation and spraying of crops to
control specific crop diseases.
According to Lucken11 the reactivity of a molecule depends in the most general way on the
polarization and polarizability of the different atoms of which it is composed. Hence it can be
expected that a systematic study of the bond and molecular polarizability coefficients can throw
light on the chemical characteristics. Similarly the knowledge of diamagnetic susceptibility (xm )
and molecular electron ionization cross section (Q), which gives a measure of the electronic
interactions between molecule and the incoming field is also expected to have some bearing on

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the activity of Antibiotics. As such a systematic study of the am , Xm and Q of a few antibiotics
is being undertaken and the results are discussed in the present investigations.
Classification
Antibiotics are classified as:
a. The producing micro-organisms
b. Activity spectrum
c. Metabolic pathways of biosynthesis
d. Chemical structure.
Garrod, Lambert and O’ Grady have classified Antibiotics on the basis of general similarity of
chemical structure
1. Penicillin and related Antibiotics:- All members of this group have a P-lactum ring in
their structure. This group includes the natural penicillins the semisynthetic penicillins
and cephalosporins.
2. Aminoglycoside Antibiotics:- All members of this group have amino sugars in glycoside
linkage. This group comprises the streptomycins, neomycin, kanamycin, paromonycin
gentamycin, tubramycin and amikacin.
3. Macrolide Antibiotics:- All these consist of a macro cyclic lactone ring to which sugars
are attached. This group comprises erythromyein, oleandomycin and spiromycin.
4. Tetracycline Antibiotics:- The Tetracyclines are derivatives of the poly cyclic
napthacene carboxamide. This group consists of tetracycline, chlortetracycline,
demeclocycline, oxytetracycline and minocycline,
5. Chloramphinicol- This antibiotic is in a class in itself. It is a nitrobenzene derivative of
dichloroacetic acid.
6. Peptide Antibiotics:- These antibiotics form a large group but very few have found
therapeutic application. These antibiotics are composed of peptide-linked amino acids
which commonly include both D-and L-forms. Antibiotics in this category include
bacitracin, gramicidin and the polymyxins.
7. Antifungal Antibiotics:- This group has two main sub-groups (1) polyenes which
contain a large ring with a conjugated double bond system. In this group most important

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antibiotics are hystain and amphotericin B, (2) the other group including 5-fluro cytosine,
clotrimazole and griseofuluin.
8. Unclassified:- These antibiotics have varied structures. They are not classified among the
main groups described above Antibiotics in this group include cycloserine, tusidic acid,
novobiocin, prasinnomycin, spectinomycin and vancomycin. In preparations of
medicines antibiotics are subdivided into the following seven groups.
i. Penicillins (including semi synthetic methicillin, oxacillin,
ii. ampicillin) and cephalosporins.
iii. Broad-Spectrum antibiotics (tetracycline and their
iv. derivatives)
v. Streptomycin group (streptomycin, neomycin etc.)
vi. Reverse antibiotics (erythromycin, chloramphenicol ristomycin, novobiocin)
vii. Antifungal (levorin, nystatin etc)
viii. antituberculous (streptimycin, kanamycin, phiorimycin, etc)
ix. Antineoplastic (bruneomycin olivomycin etc)

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Mode of Action of an antibiotic on Microorganisms
 Mechanisms of action of antibacterial drugs
A. Cell wall synthesis inhibition
1. Penicillins
A. Derivatives of 6-aminopenicillanic acid (ß-lactam ring is important structure)
B. Mechanism of action:
 Analogue of D-alanyl-D-alanine on peptide side chain of peptidoglycan à inhibits
transpeptidase from crosslinking peptidoglycan
 Binds penicillin binding proteins à activation of autolysins
C. Bactericidal
D. Effective against gram + and gram -, depending on derivative
2. Cephalosporins
a. Derivatives of 7-aminocephalosporanic acid (Fig. 33-8)
b. Similar mechanism of action as penicillins
c. Bactericidal
d. Broad spectrum
3. Bacitracin
a. Peptide
b. Mechanism of action: inhibits dephosphorylation of bactoprenol pyrophosphate
c. Bactericidal
d. Mostly effective against gram +
4. Vancomycin
a. Glycopeptide
b. Mechanism of action: prevents crosslinking of peptidoglycan by
c. Binding to the D-ala-D-ala portion of the cell wall precursor
d. Bactericidal
e. Gram +Ve

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B. Disruption of cell membranes
1. Fungal drugs
2. polymyxin B
 Basic polypeptides that act as detergents
 Mechanism of action: interact with phospholipids to increase
 Permeability and decrease osmotic integrity leakage on intracellular
 Components
 Bactericidal
 Gram –ve
C. Interference with metabolism: (Antimetabolites)
Sufadrugs (sulfonamides)
 structural analogues of p-aminobenzoic acid (Fig. 33-3, 33–4)
 mechanism of action: competes with p-aminobenzoic acid for binding to the enzyme
dihydropteroate synthetase à no folic acid synthesis à no nitrogenous base synthesis
 bacteriostatic
 broad spectrum
D. Protein synthesis inhibition
1. Tetracycline
 4-ring structure with side chains .
 Mechanism of action: reversible binding to the 30s subunit of ribosome à inhibits binding
of aminoacyl trna to ribosome à inhibition of protein synthesis
 Bacteriostatic
 Broad spectrum
2. Aminoglycosides (streptomycin, kanamycin, gentamicin)
 Group of antibiotics in which contain amino sugars and a cyclohexane ring.
 Mechanism: irreversible binding to the 30s subunit of ribosome à inhibits protein
synthesis and causes misreading of mrna
 Bactericidal
 Some are broad spectrum but mostly used against gram negatives
3 . Macrolides (erythromycin)
 12-22 carbon lactone ring linked to sugars.

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 Mechanism (erythromycin): reversibly binds 23s rrna of 50s subunit of the ribosome à
inhibits translocation during protein synthesis
 Bacteriostatic
 mostly gram +Ve
4. Chloramphenicol
 Mechanism: binds to 23S rrna of 50s subunit of the ribosome à inhibits transpeptidation
during protein synthesis
 Bacteriostatic
 Broad spectrum
E. Inhibition of nucleic acid synthesis
1. quinolones and fluoroquinolones
 Characterized by quinolone ring.
 Mechanism of action: inhibits dna gyrase à inhibition of dna replication .
 Bactericidal
 Broad spectrum
2. Rifampin
 Macrocyclic compound
 Mechanism of action: inhibits rnap à inhibition of rna synthesis
 Bactericidal
 Mostly gram +, some gram negatives
 Mechanisms ofaction of antifungal drugs
A. Selective toxicity problem
B. Polyenes
 Mechanism of action: inhibit synthesis of or interact with ergosterol à causes Membrane
permeability
 Fungicidal
C. Imidazoles
 Mechanism of action: disrupt fungal membrane synthesis and inhibit sterol synthesis
 Fungicidal

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 Mechanisms ofaction of antiviral drugs
A. Selective toxicity problem
B. Mechanisms of action based upon blocking critical steps in the virus life cycle
VII. Antimicrobial resistance
A. Molecular mechanisms
1. Decreased drug accumulation
 Prevention of entrance of drug into the cell
 Pumping drug out of cell
2. Enzymatic detoxification
3. Bypass of antibiotic resistance step
4. Altered target site
B. Origins of resistance
1. Inheritance from mother cell
2. Spontaneous mutation
3. Acquisition of plasmid (R plasmid) or transposon or phage with drug resistance gene
 Via conjugation or transformation (plasmid)
 Via transduction (phage)
 Solutions
1. Effective use of antibiotics
 Only for appropriate infections
 Dual antibiotics
 Completion of treatment
 Narrow spectrum
2. Drug discovery
3. Rational drug design