Antibiotics 3 Flashcards
History of antibacterial chemotherapy
Antibacterial remedies / herbal treatments around since ancient times.
End of 19th century - Paul Ehrlich put the search for antibacterial agents of scientific footing.
Referred to as the father of chemotherapy.
Proposed selective toxicity: said that since parasites can be differentiated from tissues from the infected host using lab dyes, these same substances might have preferential affinity for the parasites in the body as well. Showed a need to look for agents toxic to infecting micro-organisms that werent toxic to the infected host.
History of antibacterial chemotherapy: Arsphenaime
Arsphenaime: created as Ehrlich sought to make an arsenic-based compount safe for humans that was still toxic towards microbes (working on selective toxicity). Arsphenaime is an anti-spirochete which cured syphillis in rabbits but has an acceptable safety profile for humans.
- First example of effacious antibacterial but was Restricted to treat spirochete infections.
History of antibacterial chemotherapy: Prontosil
Sulphonamide bound to a red dye
initially developed to stain bacteria
Puzzled scientists as it was shown to cure mice of haemolytic streptococci infection but showed no antibacterial activity when tested in vitro.
Later discovered that in the body the compound is broken down to separate the dye component from the sulphonamide component - binding of the dye caused lack of activity ad when Prontosil was broken down the active sulphonamide compound was released.
Sulphonamides
Growth factor analogues
- Similar in structure to a growth factor required by the bacteria cell
-broad spectrum of bacteriostatic agents
Sulphanilamide
Member of sukphonamide antibiotic group
Similar in structure to para-aminobenzoic acid (PABA)
Para-aminobenzoic acid (PABA)
Precurosor of folic acid and tetrahydrofolate which is needed for DNA synthesis
Sulphanilamide aim
To compete with PABA substrate in the tetrahydrofolate biosynthesis pathway thereby preventing production of tetrahydrofolate and subsequently DNA.
Sulphonamide - selective action/toxicity
Have selective activity against bacterial cells as bacteria must synthesise folic acid - disruption of this biosynthesis pathway by antibiotics is inhibitory for bacterial cell growth.
Mammalian cells don’t require folic acid biosynthesis pathway so it is not present in mammalian systems to act as a target for these antibiotics (selective toxicity)
Why is folic acid (folate) a good target for antibiotics?
Folate is converted to dihydrofolate and then tetrahydrofolate in bacteria. Tetrahydrofolate: cofactor used by enzymes in nucleotide biosynthesis.
Tetrahydrofolate molecule cna carry one carbon group thats used to synthesise nucleotide - comprises some of the carbons used to form adenine and guanine (purines) - without folic conversion into tetrahrdrofolate Nucelotide synthesis and therefore DNA synthesis cant occur.
Sulphonamide mechanism of action - reaction
-Block folic acid synthesis at the conversin of: Dihydropterin pyrophosphate (DHPPP) + Para-aminobenzoic acid (PABA) -> Dihydropteroin (DHP)
Sulphonamide mechanism of action
- Sulphonamides act by competitively binding to the enzyme that catalyses this reaction
-Structure of sulphonamides is slightly different to PABA - it cant be used as a replacement substrate? - Cell is flooded with more sulphonamide molecules than PABA so biosynthesis is inhibited due to competitive inhibition of the dihydropholate synthase enzyme.
- Remaining folate gets used up: bacterium cannot produce purines and thymidine
requirements for sulphomaide action
depletion of folate inside the cell before effects of inhibition take effects - can take several generations to deplete making the drug slow to work.
- can be used in combination with other antibiotics (trimethoprim)
Sulphonamide side effects: Stevens Johson syndrome
- Life threatening skin condition in which cell death causes epidermis to separate from the dermis. Can be fatal
Resistance to sulphonamides - Mechanisms of resistance: Metabolic by-pass
- Metabolic by-pass: bacterial cell able to by-pass antibiotic effects by altering its metbolic processes for folic acid biosynthesis
Resistance to sulphonamides - Mechanisms of resistance: para-aminobenzoic acid
Massive increase in production of para-aminobenzoic acid - substrate outcompetes the antibiotic for tis place on the dihydropteroate synthase enzyme: sufficient production of folate occurs allowing the cell to grow.
