CHEMOTHERAPY
Chemotherapy and antibacterial drugs
Penicillins (e.g. amoxicillin, flucloxacillin, phenoxymethylpenicillin, meticillin) clavulanic acid
vancomycin
Fluoroquinolones (e.g. ciprofloxacin, moxifloxacin)
Aminoglycosides (e.g. gentamicin, streptomycin)
Macrolides (e.g. erythromycin, clarithromycin) chloramphenicol
Tetracyclines (e.g. doxycycline, lymecycline)
Sulfonamides (e.g. sulfadiazine, sulfamethoxazole) trimethoprim
• Definition of chemotherapy:
The use of drugs that are selectively toxic to treat diseases
• A fuller definition:
The use of drugs which exploit the differences between foreign cells and cells in the body (host) with
the aim of stopping the progress of a disease by killing and/or eradicating infectious agents from the
body without irreversible damage to healthy tissues
• Qualitative selective toxicity: Drug affects a target unique to the foreign cells
• Quantitative selective toxicity: Drug affects a target common to BOTH host and foreign cells,
but more effective against foreign cells
Most chemotherapy both qualitative and quantitative but just quantitative in cancer selective toxicity
(bodys own cells) – want to aim for qualitative selective toxicity
Achieving selective toxicity:
Targeting biochemical differences between host and “foreign” cells:
o Key enzymes, receptors or cellular structures (e.g. most antibiotics) – PAMPS in
bacteria – clear sites to target bacteria
o Differing replication rates (e.g. many anti-cancer drugs)
Differential distribution of the drug:
o Selective accumulation of the drug in a parasite (e.g. chloroquine in malaria)
o Selective activation of a prodrug (e.g. acyclovir by viral thymidine kinase)
o Accumulation of the drug within a restricted host compartment occupied by foreign
organism (e.g. nystatin to treat candidiasis (thrush) and other fungal infections;
mebendazole to treat nematode infections in the intestines)
,Identifying different bacteria
Originally distinguished by shape and Gram stain
Now PCR for specific bacterial DNA sequences
Gram positive (G +ve) – stained purple by Gram test
Gram negative (G -ve) – stained pink / red by Gram test
Gram-positive bacteria have a thick layer of peptidoglycan that retains the dye (purple),
while gram-negative bacteria have a higher lipid content that dissolves the dye (pink)
Commensal - living on or within another organism, and deriving benefit without harming
or benefiting the host
Basic bacterial structure
• Elevated osmotic pressure inside cells (G +ve > G -ve)
• Porins in outer membrane of G –ve bacteria allow hydrophilic molecules into the
periplasmic space
• Gram positive have thick peptidoglycan wall and plasma membrane that is stained by
gram stain
• Gram negative have outer lipid membrane that does not stain and thin cell wall with less
peptidoglycan
• Water will tend to want to enter bacteria , will swell to limit provided by cell wall
When do bacterial infections occur?
• Physical and immune barriers to infection – Infection when barriers are disrupted
• Disruption of physical barriers:
o Cuts
o Burns
o Surgery
• Human movement of bacteria to less protected areas:
o Placement of cannulae / catheters
o Urinary tract infections
• Immunosuppression:
o Loss of B cells (chronic lymphoid leukaemia) – S. pneumoniae
, o Loss of T cells (AIDS, cancer chemotherapy) – Mycobacteria
o Loss of neutrophils (bone marrow transplant, cancer chemotherapy) – P. aeruginosa
Antibacterial drugs
• Antibacterials are not necessarily Antibiotics
Antibiotics (derived from micro-organisms)
Synthetic (chemically synthesised in the laboratory)
Semi-synthetic (chemical modifications of antibiotics
• "Antibacterial" refers to any substance or compound that has the ability to kill or inhibit the
growth of bacteria. This includes not only antibiotics but also other types of antibacterial
drugs, such as antiseptics, disinfectants, and some types of chemotherapeutic agents
• While all antibiotics are antibacterials, not all antibacterials are antibiotics.
• Bactericidal (kill bacteria) vs. bacteriostatic (arrest growth of bacteria)
• Bacteriostasis allows immune system to clear remaining bacteria
• General rule: disruption of cell wall kills bacteria (bactericidal) due to osmotic lysis, whereas
inhibition of anabolic processes is bacteriostatic
Treatment AND prevention
• Antibacterials used to treat infections in every organ system
• Also used in prophylaxis of infection:
o e.g. following animal bites
o e.g. during / following surgeries
o e.g. in those in contact with infected individuals (pertussis, tuberculosis)
o e.g. in farm animal feed
, Selecting appropriate targets
Aiming for qualitative rather than quantitative toxicity – to minimise side effects
• Target cell structures / bacterial proteins not present in mammals (eukaryotic cells)
• Inhibit bacterial cell wall (unique to prokaryotes) synthesis
o penicillins, cephalosporins, vancomycin, cycloserine
• Inhibit bacterial nucleic acid synthesis
o fluoroquinolones
• Inhibit bacterial protein synthesis
o aminoglycosides, tetracyclines, chloramphenicol, macrolides
• Act as antimetabolites (prevent nucleotide synthesis)
o sulfonamides, trimethoprim
Targeting the bacterial cell wall: peptidoglycan structure
• Peptidoglycan, a polymer of N-acetylmuramic acid (NAM) and N-acetylglucosamine
• Multiple layers of peptidoglycan make up the cell wall
Peptidoglycan synthesis:
- Peptidoglycan synthesis begins with the synthesis of precursors, small building blocks of
the peptidoglycan molecule. These precursors are then transported across the cell
membrane and assembled into a long linear chain by a series of glycosyltransferase
enzymes.
- Once the linear chain is assembled, it is crosslinked by transpeptidase enzymes to form a
three-dimensional mesh-like structure. This crosslinking is critical for the stability of the
peptidoglycan layer and the integrity of the bacterial cell wall.
- Transglycocylation and transpeptidation essential two steps in building monomer onto
extending structure
- The transpeptidase enzymes are the target of many antibiotics, including penicillins and
cephalosporins, vancomyosin.
- Work by binding to and inhibiting the transpeptidase enzymes, which prevents the
crosslinking of the peptidoglycan layer and weakens the cell wall. As a result, the
bacterial cell becomes more susceptible to osmotic pressure and may lyse, or burst.
b-lactam antibacterials
- b-lactam antibiotics prevent amide bonds forming between peptide side chains of NAM
by inhibiting transpeptidase enzymes
- Transpeptidases also called penicillin-binding proteins (PBP)
- Major groups are penicillins, cephalosporins and carbapenems
- Prevent cross linking of amino acid side chains, peptidoglycan looses its rigidity
- Two alanine's make right angle hydrocarbon bond with double bonded oxygen – this site
allows interaction with transpeptidase and cross linking
- Penicillin has similar structure allowing them to interact with the active site of
transpeptidase enzyme – will covalently bind to active site of enzyme, irreversible
inhibition of enzyme
Changes in side chains (“R” group) alters:
Chemotherapy and antibacterial drugs
Penicillins (e.g. amoxicillin, flucloxacillin, phenoxymethylpenicillin, meticillin) clavulanic acid
vancomycin
Fluoroquinolones (e.g. ciprofloxacin, moxifloxacin)
Aminoglycosides (e.g. gentamicin, streptomycin)
Macrolides (e.g. erythromycin, clarithromycin) chloramphenicol
Tetracyclines (e.g. doxycycline, lymecycline)
Sulfonamides (e.g. sulfadiazine, sulfamethoxazole) trimethoprim
• Definition of chemotherapy:
The use of drugs that are selectively toxic to treat diseases
• A fuller definition:
The use of drugs which exploit the differences between foreign cells and cells in the body (host) with
the aim of stopping the progress of a disease by killing and/or eradicating infectious agents from the
body without irreversible damage to healthy tissues
• Qualitative selective toxicity: Drug affects a target unique to the foreign cells
• Quantitative selective toxicity: Drug affects a target common to BOTH host and foreign cells,
but more effective against foreign cells
Most chemotherapy both qualitative and quantitative but just quantitative in cancer selective toxicity
(bodys own cells) – want to aim for qualitative selective toxicity
Achieving selective toxicity:
Targeting biochemical differences between host and “foreign” cells:
o Key enzymes, receptors or cellular structures (e.g. most antibiotics) – PAMPS in
bacteria – clear sites to target bacteria
o Differing replication rates (e.g. many anti-cancer drugs)
Differential distribution of the drug:
o Selective accumulation of the drug in a parasite (e.g. chloroquine in malaria)
o Selective activation of a prodrug (e.g. acyclovir by viral thymidine kinase)
o Accumulation of the drug within a restricted host compartment occupied by foreign
organism (e.g. nystatin to treat candidiasis (thrush) and other fungal infections;
mebendazole to treat nematode infections in the intestines)
,Identifying different bacteria
Originally distinguished by shape and Gram stain
Now PCR for specific bacterial DNA sequences
Gram positive (G +ve) – stained purple by Gram test
Gram negative (G -ve) – stained pink / red by Gram test
Gram-positive bacteria have a thick layer of peptidoglycan that retains the dye (purple),
while gram-negative bacteria have a higher lipid content that dissolves the dye (pink)
Commensal - living on or within another organism, and deriving benefit without harming
or benefiting the host
Basic bacterial structure
• Elevated osmotic pressure inside cells (G +ve > G -ve)
• Porins in outer membrane of G –ve bacteria allow hydrophilic molecules into the
periplasmic space
• Gram positive have thick peptidoglycan wall and plasma membrane that is stained by
gram stain
• Gram negative have outer lipid membrane that does not stain and thin cell wall with less
peptidoglycan
• Water will tend to want to enter bacteria , will swell to limit provided by cell wall
When do bacterial infections occur?
• Physical and immune barriers to infection – Infection when barriers are disrupted
• Disruption of physical barriers:
o Cuts
o Burns
o Surgery
• Human movement of bacteria to less protected areas:
o Placement of cannulae / catheters
o Urinary tract infections
• Immunosuppression:
o Loss of B cells (chronic lymphoid leukaemia) – S. pneumoniae
, o Loss of T cells (AIDS, cancer chemotherapy) – Mycobacteria
o Loss of neutrophils (bone marrow transplant, cancer chemotherapy) – P. aeruginosa
Antibacterial drugs
• Antibacterials are not necessarily Antibiotics
Antibiotics (derived from micro-organisms)
Synthetic (chemically synthesised in the laboratory)
Semi-synthetic (chemical modifications of antibiotics
• "Antibacterial" refers to any substance or compound that has the ability to kill or inhibit the
growth of bacteria. This includes not only antibiotics but also other types of antibacterial
drugs, such as antiseptics, disinfectants, and some types of chemotherapeutic agents
• While all antibiotics are antibacterials, not all antibacterials are antibiotics.
• Bactericidal (kill bacteria) vs. bacteriostatic (arrest growth of bacteria)
• Bacteriostasis allows immune system to clear remaining bacteria
• General rule: disruption of cell wall kills bacteria (bactericidal) due to osmotic lysis, whereas
inhibition of anabolic processes is bacteriostatic
Treatment AND prevention
• Antibacterials used to treat infections in every organ system
• Also used in prophylaxis of infection:
o e.g. following animal bites
o e.g. during / following surgeries
o e.g. in those in contact with infected individuals (pertussis, tuberculosis)
o e.g. in farm animal feed
, Selecting appropriate targets
Aiming for qualitative rather than quantitative toxicity – to minimise side effects
• Target cell structures / bacterial proteins not present in mammals (eukaryotic cells)
• Inhibit bacterial cell wall (unique to prokaryotes) synthesis
o penicillins, cephalosporins, vancomycin, cycloserine
• Inhibit bacterial nucleic acid synthesis
o fluoroquinolones
• Inhibit bacterial protein synthesis
o aminoglycosides, tetracyclines, chloramphenicol, macrolides
• Act as antimetabolites (prevent nucleotide synthesis)
o sulfonamides, trimethoprim
Targeting the bacterial cell wall: peptidoglycan structure
• Peptidoglycan, a polymer of N-acetylmuramic acid (NAM) and N-acetylglucosamine
• Multiple layers of peptidoglycan make up the cell wall
Peptidoglycan synthesis:
- Peptidoglycan synthesis begins with the synthesis of precursors, small building blocks of
the peptidoglycan molecule. These precursors are then transported across the cell
membrane and assembled into a long linear chain by a series of glycosyltransferase
enzymes.
- Once the linear chain is assembled, it is crosslinked by transpeptidase enzymes to form a
three-dimensional mesh-like structure. This crosslinking is critical for the stability of the
peptidoglycan layer and the integrity of the bacterial cell wall.
- Transglycocylation and transpeptidation essential two steps in building monomer onto
extending structure
- The transpeptidase enzymes are the target of many antibiotics, including penicillins and
cephalosporins, vancomyosin.
- Work by binding to and inhibiting the transpeptidase enzymes, which prevents the
crosslinking of the peptidoglycan layer and weakens the cell wall. As a result, the
bacterial cell becomes more susceptible to osmotic pressure and may lyse, or burst.
b-lactam antibacterials
- b-lactam antibiotics prevent amide bonds forming between peptide side chains of NAM
by inhibiting transpeptidase enzymes
- Transpeptidases also called penicillin-binding proteins (PBP)
- Major groups are penicillins, cephalosporins and carbapenems
- Prevent cross linking of amino acid side chains, peptidoglycan looses its rigidity
- Two alanine's make right angle hydrocarbon bond with double bonded oxygen – this site
allows interaction with transpeptidase and cross linking
- Penicillin has similar structure allowing them to interact with the active site of
transpeptidase enzyme – will covalently bind to active site of enzyme, irreversible
inhibition of enzyme
Changes in side chains (“R” group) alters:
