antibiotics

Question 1

what are antibiotics

Answer 1

• Selective poisons for microbes
  o Reserved for bacteria
  o Largest impact besides vaccines

Question 2

paul erlich–magic bullet

Answer 2

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

Question 3

salvarsan 606 used for

Answer 3

syphilisis

Question 4

salvarsan 600 failed b/c

Answer 4

• Weekly injections
• Insoluble
• 600mL each inj; required 1hr
• Syringe was used
• Intramuscular injection produced necrosis—hand amputation

Question 5

in response to salvarsan

Answer 5

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 sulfanilamideME

Question 6

prontosil mechanism of action

Answer 6

 Bacteriostatic interferes with growth
 Does not kill bacteria and only effective if patient has competent immune system

Question 7

sulfanilamide (syphilis)

Answer 7

• 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

Question 8

flemming discovered penicillin

Answer 8

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)

Question 9

penicillin mechanism of action

Answer 9

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 outsideinside
o Cell wall is the target of penicillin (doesn’t affect us b/c we don’t have cell walls)

Question 10

penicillin selectivity

Answer 10

• 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)

Question 11

allergy with penicillin

Answer 11

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

Question 12

penicillin G

Answer 12

• Isolated from mold

Question 13

penicillin G acid sensitivity limitation

Answer 13

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

Question 14

penicillin g acid resistance with heteroatoms

Answer 14

add heteroatom (o) between benzene and double bond OR NH3+ in same position

Question 15

penicillin semi-synthesis

Answer 15

core is complex and difficult to synthesize
obtain core from bio sources or
use synthetic transformation to make a new drug

Question 16

biochemical prep of 6-apa

Answer 16

• 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

Question 17

creation of artificial drug

Answer 17

• Convert penicillin G into 6-APA
• Attach acyl group to NH2 of 6-APA
  MECHANISM

Question 18

Resistance caused by

Answer 18

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

Question 19

B-lactamase

Answer 19

opens B lactam ring of penicillin and deactivates it

Question 20

Fight resistance by adding large group

Answer 20

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)

Question 21

spectrum of action

Answer 21

 Gram + and gram – bacteria
 OG penicillin made only for +
 For gram -, added branched groups (hydrophilic COOH) on LHS (pentagon where sulfur @)

Question 22

Bioavailability

Answer 22

some forms of penicillin is not H2O soluble (ampicillin) remove H from COOH to make it - for better absorption in the intestine

Question 23

charge and solubility

Answer 23

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

Question 24

prodrugs

Answer 24

 Add removable group to drug to improve absorption
 In the blood it’ll be removed to deliver the drug in its active form (neutral)

Question 25

Cephalosporins pros and cons

Answer 25

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

Question 26

 Clavulanic acid

Answer 26

* 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

Question 27

Clinical use of Clav and B lactam

Answer 27

 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

Question 28

drug-drug interactions

Answer 28

* 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

Question 29

vancomycin properties

Answer 29

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

Question 30

vancomycin mechanism

Answer 30

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

Question 31

modern antibiotic research

Answer 31

* Limited o Academia and small company * Antibiotic too cheap and available o New drugs will not make $ o New drugs not used by doctors