Principles of Antimicrobial Chemotherapy Flashcards
Chemotherapy
Applied to the use of chemicals (either natural or synthetic) to inhibit the growth/replication of ‘invading organisms’ or cancerous cells within the body.
Erhlichs discoveries
Discovered and established the concept of selective toxicity.
- Gram staining technique
Erhlichs discovery about trypanosomes
Trypanosomes were killed by Salvarsan
Trypanosomes could become resistant
Trypanosomes resistant to one agent, remained susceptible to others.
Domagk and rational development of antibiotics
He pursued a series of dyes as potential antibacterials.
Discovered PRONTOSIL : a red dye that inhibited bacteria
Jacques and Therese Trefouel found that prontosil was metabolised to sulphanilamide which was not a dye, but still active against bacteria.
Domagk’s achievement
He developed the concept of rational design of anti-bacterials.
He went on to develop anti-tuberculosis agents.
Penicillin
Was a chance discovery by Alexander Fleming.
He was unable to make enough material to make treatment possible.
So, he published the discovery as a method to select bacteria on agar.
He was aware of the potential threat of AMR.
Florey and Chain
Recognised the value of penicillin as potential treatment of bacterial infection.
Used large fermenters to create enough starting material to allow extraction of penicillin.
They worked in great secrecy during the war, later in America.
The urine of treated patients was collected and penicillin re-extracted.
Penicillin G
Semi-synthetic
Penicillin nucleus
Doesn’t exist in nature
Ampicillin
Semi-synthetic
Pre-1946 treatments
Pelargonium roots
Cod liver oil
Gold
Waksman and Schatz
Antibiotic discovery based on a theory that soil organisms may have produced agents to kill mycobacteria which were derived from soil organisms.
Thousands of soil samples were screened for the presence of factors that inhibit mycobacteria.
Streptomycin discovered.
Streptomycin
Single most effective drug against TB
The streptomycin trial
Treatment groups :
- Bed rest : 52 patients
- Streptomycin : 55 patients
The streptomycin trial short term results of deaths assessed
6 months
Bed rest : 27%
Streptomycin : 7%
P = 0.01
The streptomycin trial long term results of deaths assessed
5 years
Bed rest : 62%
Streptomycin : 58%
How many of the streptomycin patients that were tested have developed resistance ?
35 out of 41
Describe how antibiotics can be developed
Based on a theory of activity - even though it is subsequently proved to be false
As a result of chance occurrences
Describe how antibiotics can be discovered
On the basis of systematic screening of natural products.
Selective toxicity
Reduces damage to the host/normal cells [PATIENT]
Maximises damage to invading organism / cancerous cells.
Principles of selective toxicity
- Central to the use of chemotherapeutic agents is
the concept of SELECTIVE TOXICITY. These drugs are
intended to be toxic to the invading organism or
cancerous cell but be relatively harmless to the host
or normal cells. - This approach depends upon the existence of
biochemical differences between the target group of
cells and the host.
Chemotherapeutic agents
These drugs are intended to be toxic to the invading organism or cancerous cell but be relatively harmless to the host or normal cells.
Examples of different selective toxicity
Penicillins
Amino glycosides
Penicillins (example of selective toxicity)
In the absence of allergy, they have a very low toxicity and high doses can be used.
Amino-glycosides (example of selective toxicity)
They have a narrow therapeutic index thus the dose that causes toxicity is very close to the therapeutic dose.
Therapeutic index
Lethal dose 50% / Effective dose 50%
Anti-tuberculosis drugs
Isoniazid and Pyrazinamide
A number of patients will develop hepatoxicity that is not dose related and may require treatment to be stopped.
Main mechanisms of action of the main antibiotic classes
Class 1-3 reactions
Class 1 reactions
Result in the synthesis of the precursor molecules necessary for Class 2 reactions.
Precursor molecules = NH4+ and SO4 2-
Class 2 reactions
Result in the synthesis of the constituent molecules.
Constituent molecules :
- Hexosamines
- Amino acids
- Nucleotides
Class 3 reactions
Constituent molecules are then assembled into macromolecules.
- Peptidoglycan
- Proteins
- RNA
- DNA
Function of pepidoglycans
They make up the cell wall of bacteria and do not occur in eukaryotes.
The cell wall is made up from various numbers of strands of pepitdoglycans.
Structure of peptidoclycans
The strands of peptidoglycan are made up of multiples of amino-acids; N-acetylglucosamine and N-acetylmuramic acid dimers.
The n-acetylmuramic acid has a short peptide side chain (hence peptidoglycan)
The peptide side chains are cross linked to form a latticework.
Cross linking gives the cell all its strength.
Beta-lactam
Cephalosporin
TARGET : Penicillin binding proteins
MECHANISMS : Preventing peptidoglycan cross-linking
EXAMPLES: Penicillin G, Flucloxacillin, Cefoxatin
Glycopeptide
TARGET : C-terminal D-Ala-D-Ala
MECHANISMS : Prevents transglycolation and transpeptidation
EXAMPLES : Vancomycin, Teicoplanin
Cyclic peptide
TARGET : C55-isopropyl pyrophosphate
MECHANISMS : Prevents carriage of building-blocks of peptidoglycan bacterial cell wall outside of the inner membrane.
EXAMPLES : Bacitracin, Polymyxin
Phosphonic acids
TARGET : murA protein
MECHANISMS : Inhibits first stage of peptidoglycan synthesis
EXAMPLES : Fosphomycin
Lipopeptides
TARGET : Cell wall stress simulation
MECHANISMS : Calcium-dependent membrane depolarisation
EXAMPLES : Daptomycin
Function of beta lactams
Prevent the cross-linking peptides from binding to the tetra-pepide side chains.
Name some penicillins
Penicillins G and V
Beta-Lactamase-resistant penicillins
Broad spectrum penicillins
Extended spectrum penicillins
Beta-Lactamase-resistant penicillins
Methicillin
Oxacillin
Nafcillin
Cloxacillin
Dicloxacillin
Broad spectrum penicillin
Ampicillin
Amoxicillin
Extended spectrum penicillins
Carbenicillin
Ticaracillin
Azlocillin
Piperacillin
Cephalosporins
- Come from the fungus Cephalosporium Acremonium.
- Work by the same mechanisms as penicillins
- Classified by generations in the order in which they
were developed.
- 1st, 2nd and 3rd generation.
- Now can be termed by means of administration; Oral is Cephalexin, Parenteral are Cefuroxime & Cefotaxime
Bacterial Folate agonists
- SULPHONAMIDES & TRIMETHOPRIM
These are antibiotics which act through an inhibition of the folate pathway in bacteria. - Folate system important in cell metabolism
- Bacteria must make their own supply but we don’t as we get it in diet.
- This makes bacteria susceptible to drugs which interfere with folate metabolism: thus we have our ‘selective toxicity’ target.
- Sulphonamides mark the beginning of antimicrobial
chemotherapy dating back to the 1930s and preceding the penicillins.
Aminoglycosides
- Form Ionic bonds at the cell surface
- Penetrate the cell wall by a transport mechanism across the cell membrane.
- Diffuse into the cytoplasm and then binds to the bacterial ribosomes.
Examples of amino glycosides
Streptomycin
Kanamycin
Neomycin
Gentamicin
Inhibition of protein synthesis
Genetamcin :
- Binds to the ribosomes :
i. At the interface between the assembled 30s and 50s subunits.
ii. Directly to the individual subunits.
- Inhibits protein synthesis by misreading of mRNA.
Tetracyclines
- They prevent attachment of the tRNA to the acceptor (A) site on the mRNA-ribosomal complex.
- This prevents the addition of amino acids to the peptide chain.
- Unlike the aminoglycosides, they are only weakly bound to the ribosomes.
- Differences in the activity of individual tetracyclines are related to their solubility in the lipid membrane of the bacteria.
Chloramphenicol, Erythromycin and Clindamycin
Prevent the addition of new amino acids to the growing peptide chain by binding to the ribosomes.
This prevents association of the peptidyl-transferase with the amino acid and no peptide bond is formed
i.e. no transpeptidation.
May also prevent translocation of the ribosome down the mRNA template (Erythromycin).
Fluoroquinolones
Fully synthetic antibiotics
Main classes of antibacterial agents - fluoroquinolones
Broad-spectrum agents
- Ciprofloxacin
- Ofloxacin
- Norfloxacin
Narrower spectrum agents
- Nalidixic acid (first introduced and is not fluorinated)
Describe the action of nalidixic acid
- Act by inhibiting bacterial DNA Topoisomerase II also known as DNA gyrase.
- This enzyme catalyses the introduction of negative supercoil in DNA permitting transcription and replication.
Use of fluoroquinolone
Defined by spectrum of activity
Defined by pharmacokinetics
Often limited by impact on other flora
