module 4

Question 1

non classical isotere + example

Answer 1

• 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

Question 2

describe antibiotics

Answer 2

• anti life
• selective poisons for microbes: Bacteria, fungi , viruses, protozoa

Question 3

who invented the first antibiotic

Answer 3

“magic bullet” Salvarsan 606, Paul eurlich in 1907

Question 4

what was the main issue with Salvarsan 606

Answer 4

• not drug like: user friendly
• insoluble + highly toxic
• inconvenient for patient

Question 5

what was the first COMMERCIALLY successful antibiotic

Answer 5

• 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

Question 6

what 2 things to look for in competitive inhibitor

Answer 6

• 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)

Question 7

what are 80% of antibiotics

Answer 7

• penicillins, more than 30,000 synthesized
• 100 sold as drugs
• semi syntehtic natural og structure + modification

Question 8

who isolated penicillin?

Answer 8

howard florey + ernst chain, 1941

Question 9

who was the first to notice mold prevents bacterial growth? (discover mold by accident)

Answer 9

Alexander Fleming, 1929

Question 10

when did penicillin become wide spread?

Answer 10

1943

Question 11

why does penicillin target bacteria but not human cells?

Answer 11

• selectivity due to bacterial cell wall

Question 12

osmotic pressure + cell wall origin

Answer 12

• 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

Question 13

what are cell walls made of?

Answer 13

peptidoglycan structure (amino acid + polysaccharide chain)

Question 14

what is the last step in cell wall biosynthesis

Answer 14

• cross link formation
• makes rigid strong structure
• presevents molecules from sliding/moving, turns into one giant molecule

Question 15

D vs L amino acids

Answer 15

• all natural amino acids have L amino acid (dashed)
• D is rare (solid)

Question 16

what enzyme is needed for cell wall formation

Answer 16

transpeptidase

Question 17

what is the catalytic triad

Answer 17

• aspartic acid, histamine, serine

Question 18

role of the catalytic triad

Answer 18

• OH of serine is nucleophile that reacts with amide carbonyl
• aspartic acid and histamine act together to form base that deprotonates H from serine

Question 19

role of oxyanion hole in catalytic triad

Answer 19

• stabilized O- that is part of tetrahedral intermediate
• involved in amide bond hydrolysis

Question 20

what family is transpeptide part of

Answer 20

• serine protease
• same mechanism of action
• purpose is to form amide bonds

Question 21

amide hydrolysis in enzyme vs water

Answer 21

• VERY SLOW IN WATER, half-life is 100s of years

Question 22

where is antibiotic involved

Answer 22

• beta lactate opening by enzyme

Question 23

how can penicillin cause allergies?

Answer 23

• 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

Question 24

similarities between D-ALA-D-ALA
+ penicillin

Answer 24

• bonds cleaved by enzyme vs bond opened in inhibition
• negative charges
• similar side chains
• similar 3D structure

Question 25

what is the natural form of penicillin

Answer 25

• penicillin G

Question 26

what are the limitations to penicillin G

Answer 26

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

Question 27

what enzyme is used to remove side chain from penicillin

Answer 27

• amidase (from e coli)
• core called 6 APA

Question 28

define narrow spectrum of activity (PENICILLIN G)

Answer 28

• only affected few bacteria (gram positive)
• unable to penetrate through lipopolysaccharide layer surrounding gram negative bacteria
• attached hydrophilic groups to overcome this (NH2)

Question 29

describe pro drugs in bioavailability

Answer 29

• increase water solubility by ensuring molecule is charged at pH 7.4
• done by attaching removal group that blocks charged sites on drug

Question 30

common structural feature between penicillin and cephalosporin

Answer 30

• b lactam, strong electrophile which is required to react with active site OH nucleophile of transpeptidase

Question 31

advantages of cephalosporin

Answer 31

• lipophilic, broad spectrum
• [4,6] ring system less reactive, less ring strain, less electrophilic
• less allergy risk

Question 32

disadvantages of cephalosporin

Answer 32

• not orally active
• low potency, need larger doses
• use semi synthesis to improve properties

Question 33

culvulanic acid

Answer 33

• 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

Question 34

example of drug drug interaction that is bad

Answer 34

• grapefruit inhibits liver function, increases metabolites which increase toxicity, drugs in blood aren’t metabolized
• CYP450 deactivated

Question 35

vancomycin (antibiotic)

Answer 35

• 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 +