Chemotherapy of Infection Flashcards
What synthetic chemicals be used to destroy infective agents?
Trypan Red (Trypanosomiasis) Atoxyl (Trypanosomiasis) Salvarsan (Syphilis)
What must chemotherapy drugs be?
Selective
i.e. drug must kill the pathogen and not the host
What was the chemotherpeutic index defined as by Paul Ehrlich?
“minimum curative dose as a fraction of the maximum dose tolerated by patient”
What is an example of calculating therapeutic index?
Salvarsan will cure syphilis at a dose of 5mg/kg/day
A dose of 15 mg/kg/day may have severe-to-fatal toxic effects on the patient
The therapeutic index is 3
What is chemotherapy?
Use of chemicals, either natural or synthetic to
Kill or inhibit growth of infectious agents
Inhibit the growth of malignant cells
:
What are chemotherpeutic agents?
Are intended to be toxic to pathogens or cancer cells
But harmless to the host or normal cell
What is selective toxicity?
Acceptable toxicity vs benefit
All toxicity is a matter of dosage
What must chemotherapeutic agents be able to do?
Exploit difference between the host and the invading micro-organism
Or between normal cell and cancer cell
Why is difficult to achieve selectivity toxicity in cancer chemotherapy?
Cancer cells are too similar to normal host cells
In cancer side effects are more readily accepted
What are Protozoa and Helminths?
Eukaryotes
What is chemotherapy used to treat infection with?
Bacteria Viruses Fungi Protozoa Helminths Ectoparasites
What makes a drug selective?
Unique target in pathogen
Different importance of target
Different stability of target protein
Drug has higher affinity for pathogen and host enyme
How does a unique target in pathogen make a drug selective?
Identified through comparative genomics
E.g. haemoglobin degradation by Plasmodium (in eukaryote)
How does different importance of target make a drug selective?
Target present in host and in pathogen
Essential only in pathogen
How does different stability of target protein make a drug selective?
Target present and essential in host and pathogen
Target enzyme quickly replaced by host
How does a drug having a higher affinity for pathogen and host enzyme make a drug selective?
Low drug concentrations inhibit pathogen enzymes first
What is penicillin?
A naturally occuring substance produced by a micro-organism that killed other microorganisms
What is an antibiotic?
Antibiotics are specific chemical substances produced by living organisms for chemically derived from those substances that are capable of inhibiting the life processes of other organisms (kill or inhibiting growth)
Why do organisms produce antibiotics?
To defend themselves from micro-organisms such as (other) bacteria, parasites, fungi
What do some antibiotics have activity against?
Eukaryotes, parasites and fungi
What do antibiotics not work against?
Viruses
Are synthetic antibacterials such as sulphanoamide drugs or bleach antibiotics?
No
What are limitations of antibiotics?
Ineffective against viruses Ineffective against most protozoan parasites and helminths Difficult to synthesise/derivatise Can be expensive Antibiotic resistance Cannot optimise their properties
What are the key differences between bacterial and mammalian cells?
Bacterial cels require para-amino nezoic acid (PABA)- mammalian cells do not (need to get in diet, eat green vegetables)
Bacterial cells have cell walls- mammalian cells do not
Bacterial cell ribosomes have 30S and 50S sub-units- mammalian cells have 40S and 60S ribosomal sub-units
What do antibacterial agents do?
Deprive bacteria of PABA (Sulphoamides)
Inhibit cell wall synthesis (Penicillin)
Interefere with bacterial protein synthesis (Tetracycline, streptomycin)
Interfere with nucleic acid synthesis
What are sulphonamides?
First effective antibacterial agents
Bacterial cells use PABA to synthesis folic acid
What can mammalian cells not synthesise?
Folic acid
What do bacteria convert PABA into?
Folic acid using the enzyme dihydrofolate reductase
What is tetrahydrofolic acid essential for the synthesis of?
Amino acids
Pyrimidine nucleotides (thymidine)
DNA and RNA
What structure do sulphonamides resemble?
PABA
How do Sulphonamides work in the cell?
Are accepted by the enzyme converting PABA to folic acid
BUT cannot be converted in the next stage
Stop amino acid/purine/pyrimidine/nucleic acid synthesis
Sulphonamides stop bacterial growth but do not kill bacteria
What are sulphonamides?
Bacteriostatic
What is the limits of sulphonamides?
Limited use for immune-compromised patients
What are examples of sulphonamides?
Sulphacetamide
Sulphamethoxazole
What was the first antibiotic?
Penicillin
What is penicillin?
An organic compound synthesised and released by one micro-organism and which kills other micro-organisms
What does penicillin do?
Inhibit cell wall synthesis
Affect only bacteria which are actively growing
Kill bacteria: are bacteriocidal
What is the cell wall?
Polymer of glycan units cross-linked by peptides- peptidoglycan wall
What does penicillin do against cell walls?
Double activity
Inhibition of the enzyme that cross-links peptide chains in the cell wall
–> inhibition of cell wall construction
Activation of an enzyme involved in cell wall turnover
–> increased cell wall breakdown
What is peptidoglycan?
90% dry weight of gram + bacteria
Wha are tetracycline?
Inhibits bacterial protein synthesis
Competes with tRNA carrying a new amino acid for its binding site on the 30S sub-unit of the ribosome
Disrupts protein synthesis
Is bacteriostatic
What was one of the first treatments for tuberculosis?
Streptomycin and the aminoglycosides
What do streptomycin and aminoglycosides contain?
Amino-sugars, bonded by glycosidic linkage o Streptomycin o Neomycin o Kanamycin o Gentamicin o Neomycin o Paromycin
What are aminoglycosides?
Irreversible inhibitors of bacterial protein synthesis
How do aminoglycosides enter gram negative bacteria?
Via porin channels in their outer membrane
What do aminoglycosides bind to?
The 30S (small) ribosomal subunit and disrupt protein synthesis
What do aminoglycosides do?
Interfere with peptide formation
Induce mRNA misreading
Cause breakup of polysomes
What is antibiotic resistant?
Development of bacterial defences against antibacterial agents
What are some drugs that have serious problems for drug treatment of infections?
Methicilline-resistance Staphylococcus aureus (MRSA)
Tuberculosis
What are mechanisms of development?
Transfer of resistance genes between bacteria
Main mechanism is by plasmid transfer
Bacteria tha make antibiotics hold resistance genes
Resistance genes already exist- just need to be obtained
For every gene in your genome how many bacteria is there?
100 bacterial ones
How much faster is bacterial generation time than human cell generation time?
100,000x
What is sulphonamide resistance?
Bacteria develop an alternative pathway that bypasses the reaction inhibited by the Sulphonamides
Bacteria develop a Dihydropteroate synthase with normal affinity for PABA but a low affinity for sulphonamides
What is penicillin resistance?
Production of an enzyme which destroys the antibiotic- e.g.- beta-lactamase destroys Penicillin’s by breaking the beta lactam ring in the penicillin molecule
What were new penicillin’s synthesised to be?
Less sensitive to enzyme
What do penicillin reversal agents do?
Clauvulanic acid is a mechanism-based B-lactamase inhibitor combined with pencillin group antibiotics to overcome resistance
What are ABC transporters?
The bacterium produces proteins in its membrane that pump Tetracyline out of the bacterium
What can tetracyline not do in a bacterial cell?
Accumulate inside in high enough concentrations to inhibit protein synthesis
What happens during the intra erythrocytic cycle?
70-80% of the host cell Hb is degraded
What does haeme undergo?
Crystallisation, takes place in the food vacuole
What interferes with polymerisation of haem?
Quinoline
