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
