L15 - Antibacterial chemotherapy II Flashcards
4 recurring themes of antibacterial action?
substrate analogues
steric hindrance
enzyme inactivation
disruption/subversion
2 final steps of peptidoglycan synthesis?
transglycosylation
Transpeptidation
What are the 2 final steps of PG synthesis catalysed by?
PBPs
bifunctional enzymes
membrane associated
2 drug classes that interfere with cell wall biosynthesis?
B-lactams
glycopeptides
Drugs in B-lactam class?
penicillins
cephalosporins
carbapenems
Drugs in glycopeptide class?
vancomycin
teicoplanin
B-lactam mechansism of action
serine residue within active site will break apart 2 D-alaine residues
serin performs nucleophilic attack on B-lactam ring = intemrediate
PBPs are inactivated - irreversible acylation
CROSS LINKING OF PEPTIDE (PEP) SIDE CHAINS BLOCKED
What are PG hydrolases?
controlled cleavage of PG for expansion during normal growth
NOT inhibited by B-lactams = weakening of PG especially at DIVISION SITE
What does Vancomycin bind to?
D-ala-D-ala
Mode of action of vancomycin?
PRIMARILY affects transglycosylation
affects some transpeptidation
Is vancomycin active against both gram-ve and gram+ve?
NO
only active gram+ve
What is daptomycin?
cyclic lipopeptide
Mode of action of daptomycin?
interact with membrane via acyl chain
integrate - Ca2+
aggregation
membrane depolarisation, leakage
Mode of action of polymixin B and E (colisitin?
bind to LPS
disrupt IM
flip-flop
What are Sulfa drugs (sulfonamides)?
competitively inhibit DHPS
alternate substrate to PABA
create dead end complex instead of dihydropteroate
no tetrahydrofolate
Mode of action of trimethoprim?
bind to Dihydrofolate reductase
Dihydrofolic acid not made into tetrahydrofolic acid
2 important quinolones?
nalidixic acid
ciprofloxacin
What 2 enzymes do quinolones act on?
DNA gyrase
Topo IV
usualyy catalyse ATP-dependent dsDNA breakage/rejoining
Mode of action of quinolones?
base stacking interactions between quinolones and 5’ base
no rejoining of DNA molecule
Mode of action of rifampicin?
TRANSCRIPTION inhibitor
binds B-subunit of prokaryotic RNApol
interferes with initiation of transcription - ABORTIVE INITIATION (2-3 nt length)
Mode of action fo mupirocin?
substrate analogue to inhibit isoleucyl tRNA synthetase
isoleucine cannot bind so cannot be linked to tRNA - NO CHARGING
2 oxazolidinones?
Linezolid
Tedizolid
Mode of action of oxazolidonones?
Gram+ve only
binds to 50S subunit
interferes with binding/positioning of initiator tRNA in ribosomal P-site
What do macrolides consist of?
Macrocyclic lactone ring - amino sugar and another sugar attached
Most used macrolide?
azithromycin (15-membered azalide)
Macrolide mode of action?
Bind to 23s rRNA at peptide exit site in 50S subunit
block exit of growing peptides in 50S tunnel
premature dissociation of peptidyl-tRNA from P-site
Mode of action of fusidic acid?
binds to EFG
which binds to ribosome A-site and moves tRNAs through ribosome using GTP
FA locks EFG onto ribosome and prevents conformation shift needed to dissociate from ribosome
