antibiotics

Question 1

mechanisms

Answer 1

interfere with critical process or structure:
substrate analogues 
steric hindrance 
enzymatic inactivation
disruption or subversion

Question 2

selective toxicity recurring themes

Answer 2

agent doesnt get into mammalial cells
targets processes/enzymes not in mammalial cells or are different
agent is pro drug only active in bacteria

Question 3

interfere with nucleotide biosynthesis

Answer 3

sulphonamides

trimethoprim

Question 4

interfere with RNA transcription

Answer 4

Rifamycin binds RNA polymerase

Question 5

target protein synthesis

Answer 5

linezolid
fuscidic acid (not ribosomes)
macrolides 
tetracyclines 
aminoglycosides

Question 6

target cell wall synthesis

Answer 6

b lactams
cycloserine
glycopeptides

Question 7

target tropo-isomerases

Answer 7

quinolones

Question 8

target cytoplasmic membrane intergrity

Answer 8

polymyxins

daptomycin

Question 9

peptidoglycan structure and function

Answer 9

crystal lattice structure
glycan polymers of alternating NAG and NAM monomers.
peptide bridges cross link the strands
provides protection against osmotic pressure

Question 10

peptidoglycan biosynthesis final 2 steps

Answer 10

pentapeptide is used for cross linking reaction which has 2 D-ala-D-ala amino acids (resistant to proteolytic attack)
transglycosylation involves polymerization of the disaccharide with glycan strands
transpeptidation involves cross linking with pentapeptides

Question 11

penicillin binding proteins

Answer 11

catalyse transglycosylation and transpeptidation

tethered in cytoplasmic membrane

Question 12

2 antibiotic classes tht target cell wall biosynthesis

Answer 12

b lactams:
penicillins, cephalocporins.
glycopeptides
vancomycin, teicoplanin

Question 13

penicillin

Answer 13

has a D-alanyl-Dalanine in the B lactam ring - so bind Penicllin Binding Proteins (analogue to natural substrate)
inactivates the enzyme - binds the serine residue which causes nucleophillic attack on the ring, opening it up and it becomes contently attached to active site serine - enzyme no longer active
transpeptidation blocked - cell wall loses integrity

Question 14

peptidoglycan hydrolases

Answer 14

bacterial enzymes
break bonds within peptidoglycan at the division site. Not inhibited by b lactams
breaks down cell wall
osmotic lysis

Question 15

vancomycin

Answer 15

binds D-ala D-ala of peptidoglycan precursor
forms hydrogen bond network - binds to precursor to occludes it and prevents it being used as a substrate for PBP.
prevents transglycosylation (not incorporated into glycan strands) and transpeptidation
narrow spectrum - only active against gram positive
cannot get through outer membrane porin (1500 daltons), so cannot access peptidoglycan in gram negative

Question 16

Cycloserine

Answer 16

competitive inhibitor of enzymes that synthesise and ligate the D-alanines

Question 17

selective toxicity of beta lactams

Answer 17

mammalians dont have PBPs or cell walls

Question 18

daptomycin

Answer 18

gram positives membrane integrity disruption
cyclical head group and lipophilic tail
lipophilic tail inserts into membrane
reliance on calcium ions to reduce repulsion by negative charge of head group and cell membrane
aggregate
physical disruption of membrane
membrane depolarization and leakage of content

Question 19

polymycin B and E

Answer 19

specific for gram negatives
make contact with LPS
translocated through outer membrane
toxic

Question 20

selective toxicity of daptomycin

Answer 20

different membrane compositions of mammalian and bacterial

Question 21

sulfonamides

often used with trimethoprim = co-trimoxozole = synergism

Answer 21

target nucleotide metabolism
synthetic
target tetrahydrofolate biosynthesis pathway, generates dTMP - precursor for DNA synthesis
inhibit GTP -> dyhyropteroate. analogous to PABA substrate for DHPs. enzyme binds to sulfonamides and produces a dead-end complex
uses up enzyme , waste resources

Question 22

Trimethoprim

Answer 22

competitive inhibitor
(analogue of dihydrofolate acid)
binds dihydrofolate reductase
higher affinity for bacterial enzyme than mammalian

Question 23

sulfonamide selective toxicity

Answer 23

humans obtain intermediates from diet - dont undergo pathway

Question 24

quinolones

Answer 24

interfere with nucleotide biosynthesis, block DNA synthesis
act on 2 enzymes - topoisomerases DNA gyrase and DNA tropoisomerase 4
both catalyse ATP dependent DNA double strand break/rejoining reactions, achieves super coiling
quinolones similar to bases - base stacking interactions, binds quinolone binding pocket
enzyme cannot resolve structure - double strand breaks accumulate
DNA synthesis shuts down, cell death

Question 25

quinolones selective toxicity

Answer 25

Mammalians dont have DNA gyrase | quonolones affinity for bacterial troposimerase higher

Question 26

Rifampycin

Answer 26

only inhibitor that targets transcription target is RNA polymerase binds beta subunit of prokaryotic RNA pol. occludes the exit tunnel causes abortive initiation of transcription, DNA cannot pass through

Question 27

rifampycin selective toxicity

Answer 27

prokaryotic RNA pol is structurally different to mammalian

Question 28

targeting protein synthesis

Answer 28

mostly bind ribosomes mostly bacteriostatic mostly interfere with elongation step

Question 29

selective toxicity of protein synthesis inhibitors

Answer 29

selective toxicity comes from the difference between prokaryotic and eukaryotic ribosomes prokaryotic - 70S made up of 50S and 30S subunits eukaryotic - 80S made up of 40S and 80S

Question 30

mupirocin

Answer 30

inhibits formation of isoleucyl tRNA - interferes with charging 8000 times more affinity for bacterial

Question 31

linezolid

Answer 31

binds to the A site of the 50s ribosome prevents attachment of incoming amino acyl tRNA used for MRSA infection

Question 32

macrolides

Answer 32

natural product but modified azithromycin has expanded spectrum -used in respiratory infection and chlamydial infection binds to the 23s rRNA peptide exit site in the 50S subunit, blocks peptide leaving causes premature termination

Question 33

fusidic acid

Answer 33

binds to Elongation Factor G (EF-G) EF-G allows translocation of mRNA through ribosome. binding of fusidic acid binds EF-G, cannot dissociate from ribosome acceptor site, materials cannot be delivered to ribosome

Question 34

selective toxicity

Answer 34

preferentially accumulates inside bacterial cells