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Summary CIPT minor week 6
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Summary of 8 pages for the course Minor Cancer-Immunity-Personalized therapies at VU (CIPT minor week 6)
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Week 6: Infection and immunity IIIHistory of antibiotics
Antimicrobials are one of the most successful medications ever because of their huge
benefits, low toxicity and costs.
Discovery of drugs:
● Arsenobenzenes + amino group → Salvarsan compound 606. Used to treat syphilis.
● Prontosil → used against streptococci. Nobel prize 1939.
● Prontosil’s active form was Sulfanilamide → involved in the inhibition of folate
biosynthesis.
● Penicillin → used in the war, mainly against soldiers with gonorrhoea instead of big
wound infections (because they cannot enter the field quickly.
Actinomycetes: When spores have a limited
supply of food, they degrade their hyphae to
get nutrients for the formation of new spores
→ but are vulnerable to others that want
nutrients. Therefore they produce antibiotics
as protection from bacteria = Waksman
screening platform
● Streptomycin is produced from a spore → first medicine against M. tuberculosis.
Now we have an antibiotic innovation gap:
● Scientifically: low-hanging fruit has been
picked.
● Economically: poor return on investment
● Regulatory: approval of new drugs has become
more difficult.
Overview of currently used antibiotics
The cell wall is important for the activity of antibiotics.
Gram-positive (one membrane) are therefore more
easily killed.
● Gram + = S. aureus & Streptococcus
● Gram - = E.coli, Salmonella, Klebsiella
pneumoniae.
So, therefore different antibiotics work on different
bacteria with different membranes. Special bacteria
are Chlamydia, Rickettsia and Mycobacteria.
Picture:
Bactericidal antibiotic = an
antibiotic that kills the bacteria.
Bacteriostatic antibiotic = an
antibiotic that inhibits growth.
Many antibiotics have been
discovered as natural compounds.
, 1st generation antibiotics: were not invented as medicine, just happen to work against
pathogens.
2nd generation antibiotics: tetracyclines → lower toxicity and can be manufactured to
change the working spectrum of the antibiotic.
3rd generation antibiotics: when bacteria develop resistance, these are needed. Can be
done to improve existing antibiotics by adding minor modifications.
B-lactam is the most important group of antibiotics ever discovered.
● B-lactam antibiotic (1e): Penicillin is an example.
○ Used to work against gram + like streptococci and some gram - like N.
meningitides.
○ The target is the peptidoglycan biosynthesis
○ More examples are:
■ Amoxicillin: good bioavailability → oral administration. excellent by
gram+
■ Flucoxallin: resistant to the action of penicillinase (made by bacteria to
prevent the action of penicillin). For infections of S.aureus.
■ Piperacillin: broad gram- activity like P.aeruginosa.
● B-lactam antibiotic (2e): Cephalosporins.
○ Originate from a natural compound, looks a lot like penicillin but with an R
group
○ Used in hospitals, mostly IV administration.
● B-lactam antibiotic (3e): Carbapenems
○ Natural compound.
○ Very broad gram +/-/ anaerobic activity
○ Agents of the last resort
● Resistance against B-lactam: beta-lactamases = hydrolysed the beta-lactam.
○ Can be inhibited by clavulanic acid or tazobactam
New antibiotics: working at the ribosome.
○ Aminoglycosides: against most gram -/staphylococci but not anaerobic.
Reading of the mRNA incorrectly.
○ Tetracyclines: very broad. Interfere in the tRNA and mRNA complex.
○ Macrolides: binds to the 50S portion → no translocation. Excellent
bioavailability.
○ Chloramphenicol: inhibits the formation of the peptide bond. Excellent
bioavailability.
DNA gyrase inhibitor: binding to DNA gyrase and topoisomerase IV → inhibition of the DNA
unwinding and DNA double-strand breaks.
○ The prodrug Metronidazole is reduced under anaerobic conditions.
○ Antabuse reaction to alcohol
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