ABX II inhibitors of peptidoglycan synth Flashcards
5 inhibitors of peptidoglycan synthesis
- beta-lactams (eg penicillin)
- vancomycin
- Fosfomycin
- cycloserine
- Bacitracin
why do bacteria have peptidoglycan?
it’s a rigid layer around the cell so h2o stays out and the cells can’t lyse
what are cell wall synthesis inhibitors?
drugs that block enzymes that synthesize peptidoglycan (usually bactericidal!)
components of a Gram + cell vs a gram - cell
gram +: capsule with teichoic and lipoteichoic acids, thick peptidoglycan, cyctoplasmic membrane
gram -: capsule, LPS, outer membrane with porins, very thin peptidoglycan, cytoplasmic membrane
structure of peptidoglycan
a chain of 2 sugars: N-Acetyl muramic acid (NAM) + N-acetyl-glucosamine (NAG) bound to each other with tetrapeptide chains (the 3rd aa on one chain links to the 4th aa on the other)
4 steps in peptidoglycan synth:
- assemply of peptidoglycan monomers
- transport peptidoglycan monomers
- polymerization of peptidoglycan
- cross linking peptidoglycan polymers
2 parts of assemby of peptidoglycan monomers
- get the peptide chain together: L-alanine —> D-alanine via racemase. D-alanine + another peptide monomer —> dimer via ligase which is added to the peptide chain
- Glucose —> NAG —-> NAM —> connected to peptides
the conversion of NAG —> NAM is facilitated by what enzyme?
PEP (phosphoenolpyruvate)
the conversion of L-ala —> D-ala is facilitated by what enzyme?
The addition of D-ala to another peptide is facilitated by what enzyme:
conversion: racemase
combination: ligase
which Abx inhibit monomer synthesis of peptidoglycan
Cycloserine (inhibits racemase and ligase so peptide chain can’t be made) and Fosfomycin (PEP analogue that inhibits NAG —> NAM so sugar chain can’t be made)
Fosfomycin what is it and what is it used for
PEP analogue that inhibits NAG—> NAM so blocks assemply of peptidoglycan monomers
used against enteric Gram neg rods, particularly UTIs (because it’s excreted unchanged in the urine so there’s a high concentration in the urinary tract)
Cycloserine what does it block and what is it used for?
a D-ala analogue that blocks racemase and ligase so peptide monomers of peptidoglycan can’t be formed.
used for highly resistant mycobacteria (when they run out of other options)
side effects associated with cycloserine
neurological side effects (confusion, psychosis). used as a last resort!!
normal process for peptidylglycan transport
NAM + peptide chain binds bactoprenol. NAG binds NAM, the mature disaccharide is lipid soluble and flips to the outside of the membrane
how does Bacitracin work?
it binds bactoprenol so that NAM can’t so the peptidoglycan monomers can’t be transported outside of the cell
Bacitracin is effective against what bacteria?
gram positive bacteria (it can’t pass through the gram - porins!)
how is bacitracin used?
only topically (ie neosporin) because of neurotoxicity
Describe normal peptidoglycan polymerization
the peptidoglycan monomer that is newly outside of the cell is added to a growing sugar chain by transglycosylase
what does vancomycin do? how does it work
it inhibits transglycosylase so that newly extracellular peptidoglycan monomers can’t be added to long sugar chains. It does this by bingind to the D-ala peptides at the top of the peptide chain
what is vancomycin effective agst?
what are imp exceptions?
almost all gram + bacteria
Imp exceptions: some enteroccoci and some rare S. aureus
is vancomycin effective agst gram neg bacteria?
NO because too big to pass through the porins
what is vancomycin used for?
empiric therapy of significant infection
specific therapy of enterococci, staphylococci and strep that is resistant to other peptidoglycan synth inhibs but not vancomycin)
oral admin for C diff colitis
why can oral vancomycin be used for C diff?
because it’s not absorbed so it will stay i the gi tracts
what is the common adverse effect of vancomycin and how can you avoid it (3)
what are uncommon adverse effects of vancomycin (2)
common:
1. red man/red neck syndrome: histamine release —> erythema, pruritis (itchiness) of head, neck, trunk, with hypotension. Not mediated by Abs.
avoid with slow IV infusion or antihistamines
- uncommon:
neutropenia
nephrotoxicity (increased aminoglycosides)
normal process of peptidoglycan cross linking
after transglycosylase takes a peptidoglycan monomer and attaches it to a longer sugar chain, transpeptidase 1. binds the 2 D-ala on peptide chain, 2. cleaves of 1 D-ala and 3. links the remaining D-ala to the 3rd aa of another
the most important enzyme for peptidoglycan cross linking
transpeptidases, which are Penicillin binding proteins
B-lactam mechanism
it resembles D-ala-D-ala and binds PBP as a “suicide substrate”
spectra of B-lactams depends on
- ability to reach the transpeptidase (ie too big to get through porin of gram neg)
- the affinity for an essential transpeptidase (PBP) (a high affinity = lots of killing/ low MIC, low affinity = no killing/lg MIC)
- whether B lactam is cleaved by B-lactamase, a bacterial defense mech
4 categories of B-lactams (which block transpeptidases/cross linking of peptidoglycans)
- penicillins
- cephalosporins
- monobactam
- carbapenems
3 categories of penicillins
- natural penicillins (G & V)
- staph - penicillinase resistant penicillins
- aminopenicillins
natural penicillins G and V are usually/always useful for:
often useful for:
sometimes useful for:
natural penicillins G and V are usually/always useful for: Grp A/B strep
often useful for: S. pneumo and N. Menigitidis
sometimes useful for: Enterococcus
what are penicillinase-resistant penicillins
these are penicillins that are resistant to B-lactamase made by staphylococci because of their bulky side groups which lower their affinity for B-lactamase
Penicillinase resistant penicillins are only used to treat
staph
what are Aminopenicillins
these are penicillins with a charged amino group so they pass through porins. They can bind the Penicillin binding proteins of enterococci and listeria
what can aminopenicillins be used to treat?
everything penicillin is used for (except N. meningitidis): Strep A/B, S. pneumo, Enterococci (even better than penicillin)
PLUS: Listeria, Enteric Gram neg rods, and Haemophilus
Beta-lactamase inhibitors what are they and how are they used?
what: weak B-lactams which irreversibly bind to some B-lactamase
how: in combo with B-lactams to improve effectiveness
-
adverse effects of penicillins
- an allergic response to IgE = common (2-8%) —> pruritis, flushing, wheezing, hypotension and shock
- less common: hemolytic anemia, thrombocytopenia and nephritis
is the antibody response against penicillin during an allergic response due to the B-lactam ring, or other parts of the molecule?
other parts
how do you deal with penicillin hypersensitivity?
choose a non-B lactam drug if possible.
If not, skin test for PCN allergy and desensitize if positive (administer small doses to use of all the IgE), or use beta-lactam if negative
Cephalosporins– how are they different from penicillin
the R1 group affects their affinity for PBP and B-lactamase —> which changes the spectrum of activity
the R2 group affects their distribution (eg CSF) and half life of the drug
what are each generation of cephalosporins most effective in battling?
first: skin/soft tissue damage, Staph and Strep A/B
2nd gen: resp ifxns, anaerobic ifxn
3rd gen: meningitis, gonorrhea, serious resp ifxns and GNR
4th gen: Ifxns with resistant GNRs (Enteric GNRs and P aerug)
ceftaroline
a 3rd gen cephalosporin that’s effective agst MRSA. It’s as effective as standard therapy for omplex skin and soft tissue ifxns, slightly more effective than standard therapy for community-acquired pneumonia
adverse effects of cephalosporins
allergy– les common than allergies to penicillin, but an allergy to penicillin increases the risk of allergies to cephalosporins
rare GI sideeffects are not very severe
Carbapenems
a type of B-lactam that binds to PBP of GP and GN bacteria, and is resistant to almost all B-lactamases and cross the outer membrane via a different porin than other b-lactams
Carbapenem use
broad empiric therapy (effective for GP and GN and resistant to almost all B lactamases)
provided as specific therapy for P aerug and Enteric GNR
Pharmokinetics of B-lactams
- most Beta-lactams are excreted in the urine unchanged —> can be used to treat UTIs
- oral doses don’t reach adequate levels in the CNS, but in the presence of inflammation penicillin ampicillin, carbapenems and 3rd and 4rth generation cephalosporins reach adequate levels in the csf
which peptidoglycan synthesis inhibitors block the assembly of monomers
cycloserine (block racemase and ligases)
fosfomycin (PEP analogue that blocks NAG—> NAM
which peptidoglycan synth. inhib blocks transport of peptidoglycan monomers?
bacitracin
which peptidoglycan synth. inhib blocks polymerization of peptidoglycan subunits?
glycopeptides (vancomycin)
which peptidoglycan synth. inhib blocks cross linkage of peptidoglycan poymers?
B-lactam drugs
