module 4 Flashcards
non classical isotere + example
- atoms or groups with bio/chem similar properties
- differ in electronics or steric but behave similarly in biological systems
- carboxylic acid replaced by acidic groups with similar pkas
describe antibiotics
- anti life
- selective poisons for microbes: Bacteria, fungi , viruses, protozoa
who invented the first antibiotic
“magic bullet” Salvarsan 606, Paul eurlich in 1907
what was the main issue with Salvarsan 606
- not drug like: user friendly
- insoluble + highly toxic
- inconvenient for patient
what was the first COMMERCIALLY successful antibiotic
- prontosil or sulfanilamide (active form of drug)
- effective because of metabolism
- bacteriostatic: interferes with bacterial growth, doesn’t kill bacteria
- prevents bacteria from making coenzyme F
what 2 things to look for in competitive inhibitor
- binds better than natural substrate (nature does not make optimal systems otherwise drugs not possible)
- basis for selectivity in humans (humans lack enzyme that bacteria has)
what are 80% of antibiotics
- penicillins, more than 30,000 synthesized
- 100 sold as drugs
- semi syntehtic natural og structure + modification
who isolated penicillin?
howard florey + ernst chain, 1941
who was the first to notice mold prevents bacterial growth? (discover mold by accident)
Alexander Fleming, 1929
when did penicillin become wide spread?
1943
why does penicillin target bacteria but not human cells?
- selectivity due to bacterial cell wall
osmotic pressure + cell wall origin
- high concentration inside, low outside, creates gradient
- cannot move stuff from inside out due to membrane
- move water outside in to reduce concentration inside
- moving water in increases pressure
- large cells have low internal pressure (human cells)
- small cells have high pressure, so they don’t explode, extra structures required to contain pressure + resist high osmotic pressure
what are cell walls made of?
peptidoglycan structure (amino acid + polysaccharide chain)
what is the last step in cell wall biosynthesis
- cross link formation
- makes rigid strong structure
- presevents molecules from sliding/moving, turns into one giant molecule
D vs L amino acids
- all natural amino acids have L amino acid (dashed)
- D is rare (solid)
what enzyme is needed for cell wall formation
transpeptidase
what is the catalytic triad
- aspartic acid, histamine, serine
role of the catalytic triad
- OH of serine is nucleophile that reacts with amide carbonyl
- aspartic acid and histamine act together to form base that deprotonates H from serine
role of oxyanion hole in catalytic triad
- stabilized O- that is part of tetrahedral intermediate
- involved in amide bond hydrolysis
what family is transpeptide part of
- serine protease
- same mechanism of action
- purpose is to form amide bonds
amide hydrolysis in enzyme vs water
- VERY SLOW IN WATER, half-life is 100s of years
where is antibiotic involved
- beta lactate opening by enzyme
how can penicillin cause allergies?
- good electrophile can react with nucleophilic side chains (serine protease or other proteins)
- changes shapes of proteins which body doesn’t recognize and therefore allergic reaction
- stronger allergic reactions second type
similarities between D-ALA-D-ALA
+ penicillin
- bonds cleaved by enzyme vs bond opened in inhibition
- negative charges
- similar side chains
- similar 3D structure
what is the natural form of penicillin
- penicillin G
what are the limitations to penicillin G
1) acid sensitivity
- very acidic
- structure changes in stomach environment
- no longer OG properties/efficiency
- must be given by IV
- for acid resistance, add EWG (AMINE)
2) resistance ;3
3) spectrum of action
4) bioavailability
what enzyme is used to remove side chain from penicillin
- amidase (from e coli)
- core called 6 APA
define narrow spectrum of activity (PENICILLIN G)
- only affected few bacteria (gram positive)
- unable to penetrate through lipopolysaccharide layer surrounding gram negative bacteria
- attached hydrophilic groups to overcome this (NH2)
describe pro drugs in bioavailability
- increase water solubility by ensuring molecule is charged at pH 7.4
- done by attaching removal group that blocks charged sites on drug
common structural feature between penicillin and cephalosporin
- b lactam, strong electrophile which is required to react with active site OH nucleophile of transpeptidase
advantages of cephalosporin
- lipophilic, broad spectrum
- [4,6] ring system less reactive, less ring strain, less electrophilic
- less allergy risk
disadvantages of cephalosporin
- not orally active
- low potency, need larger doses
- use semi synthesis to improve properties
culvulanic acid
- not an antibiotic
- does not inhibit transpetidase
- does not kill bacteria
- targets b lactamase, stops breaking of penicillin
- selectivity for b lactamase
- example of drug - drug interaction
example of drug drug interaction that is bad
- grapefruit inhibits liver function, increases metabolites which increase toxicity, drugs in blood aren’t metabolized
- CYP450 deactivated
vancomycin (antibiotic)
- binds strongly to D-ALA - D-ALA
- inhibits substrate instead of enzyme
- enzyme does not interact with substrate
- USED AS LAST RESORT
- ## ONLY WORKS ON GRAM +
