antibiotics Flashcards
what are antibiotics
- Selective poisons for microbes
o Reserved for bacteria
o Largest impact besides vaccines
paul erlich–magic bullet
o Penicillin circulates in body magically finds bacteria and kills it w/o harming the rest of the body
o Trypan red effective against trypanosomes
salvarsan 606 used for
syphilisis
salvarsan 600 failed b/c
- Weekly injections
- Insoluble
- 600mL each inj; required 1hr
- Syringe was used
- Intramuscular injection produced necrosis—hand amputation
in response to salvarsan
Domagk made prontosil
o Effective in vivo not in vitro
o Effective because of metabolism
It is altered in the liver by cutting it (prontosil) in half to get sulfanilamideME
prontosil mechanism of action
Bacteriostatic interferes with growth
Does not kill bacteria and only effective if patient has competent immune system
sulfanilamide (syphilis)
- Inhibit coenzyme F synthesis
- Competitive inhibitors of PABA
o Competes with p-aminobenzoic acid for active site
o Enzyme cannot tell the difference between drug and PABA and the rxn does not occur
o The inhibitor binds to the enzyme better than the natural substrate
Nature is not optimal, if so drugs would not be possible
Humans lack the enzyme and get it from tetrahydrofolate from folic acid in diet
flemming discovered penicillin
by accidentally contaminating culture with mold
mold prevented bacterial growth
mold selectively killed types of bacteria
Florey and chain isolate penicillin
* used mice (1/2 w/penicillin and the other w/o, noticed the first half alive and the other dead)
penicillin mechanism of action
o Bacterial cell small and have internal pressure, the cell wall helps resist the osmotic pressure (a lot of solute inside than outside of the cell [C] gradient)
o Water moves outsideinside
o Cell wall is the target of penicillin (doesn’t affect us b/c we don’t have cell walls)
penicillin selectivity
- Humans don’t have cell walls
o No equiv enzyme
o D-ala link is unique in nature
In bacteria only
All AA have L configuration (serine uses)
allergy with penicillin
penicillin is a good electrophile that can acylate host serine proteases that are tagged by the immune system. the penicillin ring opens. the strongest reaction occurs the 2nd time taking the drug
penicillin G
- Isolated from mold
penicillin G acid sensitivity limitation
when penicillin reacts with acid, the ring opens up, the double bonded O makes a pentagon and the square is opened up through the mechanism
penicillin g acid resistance with heteroatoms
add heteroatom (o) between benzene and double bond OR NH3+ in same position
penicillin semi-synthesis
core is complex and difficult to synthesize
obtain core from bio sources or
use synthetic transformation to make a new drug
biochemical prep of 6-apa
- Grow penicillin mold
- Extract penicillin G
- Use amidase enzyme form E.coli to remove side chain (draw mechanism
*6-apa is the active part of penicillin
creation of artificial drug
- Convert penicillin G into 6-APA
- Attach acyl group to NH2 of 6-APA
MECHANISM
Resistance caused by
by mutations in transpeptidase (changes in active site that excludes penicillin)
Bacteria evolve to get rid of drug
* Actively transport out the cell
* Destroy drug
* Antibiotic resistance by beta-lactamase
B-lactamase
opens B lactam ring of penicillin and deactivates it
Fight resistance by adding large group
add large ringed (benzene with OMe on ortho and para )
this allows penicillin to fit into active site of transpeptidase and not B lactamase (b/c B lactamase AS is too small)
spectrum of action
Gram + and gram – bacteria
OG penicillin made only for +
For gram -, added branched groups (hydrophilic COOH) on LHS (pentagon where sulfur @)
Bioavailability
some forms of penicillin is not H2O soluble (ampicillin) remove H from COOH to make it - for better absorption in the intestine
charge and solubility
if drug is + and -, it is not soluble in and it must be - charged to bind to transpeptidase. so must cover up - with R group to incr H2O solubility and once it goes through the blood - will come back
prodrugs
Add removable group to drug to improve absorption
In the blood it’ll be removed to deliver the drug in its active form (neutral)
Cephalosporins pros and cons
pros: o Lipophilic
o [4.6] ring less reactive than [4,5]
Fight against resistant strains
Less allergy
cons:o Not orally active
o Larger dose=larger pill=low potency
o Use semi synthesis to improve properties
o Semi syn to improve (EWG, Big group, branching group)
o Modify properties
Clavulanic acid
- Non antibiotic
o Does not inhibit transpeptidase
o Does not kill bacteria
o Bacteria uses B-lactamase to destroy antibiotics
so clav destroys B lactamase
MECHANISM
Clinical use of Clav and B lactam
Use with B-lactam that is sensitive to B-lactamase
Clavulanic acid
* Inhibits B-lactamase
* Protects antibiotic from the resistance enzyme
B-lactam antibiotic
* Inhibits transpeptidase
* Kills bacteria
drug-drug interactions
- One drug change the bioavailability of another
o A drug taken w/ another drug that effects amount of drug that is bioavailable (clav and penicillin)
o Grapefruit inhibits liver function (Bergamottin)
Metabolize by the liver
Metabolite irreversibly binds a glutamine on CYP
CYP is deactivated
vancomycin properties
o Glycopeptide
o Sugars
o Short protein w/ 7 AA’s
o Aromatic rings on peptide are linked forming bow shaped structure
o Hole shaped molecule, wraps around itself binds to substrate of transpeptidase
vancomycin mechanism
o Binds strongly to D-Ala-D-Ala tail of peptide
o Prevents transpeptidase from binding
Prevents cell wall cross linking
Enzyme inhibition by substrate binding
* Inhibitor bound to substrate, enzyme cannot interact with substrate and its function is blocked
o Last resort drug
o Used for infections with bacteria that resistant
o Works only on gram + bacteria
Large molecule
Not lipophilic enough
modern antibiotic research
- Limited
o Academia and small company - Antibiotic too cheap and available
o New drugs will not make $
o New drugs not used by doctors
