antibiotics Flashcards
mechanisms
interfere with critical process or structure: substrate analogues steric hindrance enzymatic inactivation disruption or subversion
selective toxicity recurring themes
agent doesnt get into mammalial cells
targets processes/enzymes not in mammalial cells or are different
agent is pro drug only active in bacteria
interfere with nucleotide biosynthesis
sulphonamides
trimethoprim
interfere with RNA transcription
Rifamycin binds RNA polymerase
target protein synthesis
linezolid fuscidic acid (not ribosomes) macrolides tetracyclines aminoglycosides
target cell wall synthesis
b lactams
cycloserine
glycopeptides
target tropo-isomerases
quinolones
target cytoplasmic membrane intergrity
polymyxins
daptomycin
peptidoglycan structure and function
crystal lattice structure
glycan polymers of alternating NAG and NAM monomers.
peptide bridges cross link the strands
provides protection against osmotic pressure
peptidoglycan biosynthesis final 2 steps
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
penicillin binding proteins
catalyse transglycosylation and transpeptidation
tethered in cytoplasmic membrane
2 antibiotic classes tht target cell wall biosynthesis
b lactams:
penicillins, cephalocporins.
glycopeptides
vancomycin, teicoplanin
penicillin
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causes nucleophillic attack on the ring, opening it up and it becomes contently attached to active site serine - enzyme no longer active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
peptidoglycan hydrolases
bacterial enzymes
break bonds within peptidoglycan at the division site. Not inhibited by b lactams
breaks down cell wall
osmotic lysis
vancomycin
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
Cycloserine
competitive inhibitor of enzymes that synthesise and ligate the D-alanines
selective toxicity of beta lactams
mammalians dont have PBPs or cell walls
daptomycin
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
polymycin B and E
specific for gram negatives
make contact with LPS
translocated through outer membrane
toxic
selective toxicity of daptomycin
different membrane compositions of mammalian and bacterial
sulfonamides
often used with trimethoprim = co-trimoxozole = synergism
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
Trimethoprim
competitive inhibitor
(analogue of dihydrofolate acid)
binds dihydrofolate reductase
higher affinity for bacterial enzyme than mammalian
sulfonamide selective toxicity
humans obtain intermediates from diet - dont undergo pathway
quinolones
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
quinolones selective toxicity
Mammalians dont have DNA gyrase
quonolones affinity for bacterial troposimerase higher
Rifampycin
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
rifampycin selective toxicity
prokaryotic RNA pol is structurally different to mammalian
targeting protein synthesis
mostly bind ribosomes
mostly bacteriostatic
mostly interfere with elongation step
selective toxicity of protein synthesis inhibitors
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
mupirocin
inhibits formation of isoleucyl tRNA - interferes with charging
8000 times more affinity for bacterial
linezolid
binds to the A site of the 50s ribosome
prevents attachment of incoming amino acyl tRNA
used for MRSA infection
macrolides
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
fusidic acid
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
selective toxicity
preferentially accumulates inside bacterial cells
