Antibiotics Against Cell Wall Synthesis Flashcards
broad spectrum vs extended spectrum
broad spectrum: work against both Gram+ and Gram- bacteria
extended spectrum: selectivity is broadened by chemical modification
why don’t larger drugs typically work on Gram- bacteria?
outer lipid membrane of Gram- bacteria is relatively impervious - transport of drugs through transmembrane pores favores small hydrophilic drugs
in the peptidoglycan layer of bacteria:
______ enzymes join the sugars that make polysaccharide chains
and
______ enzymes join the sugar-linked peptides to x-link polysaccharide chains
Transglycosylase enzymes join the sugars that make polysaccharide chains
and
Transpeptidase enzymes join the sugar-linked peptides to crosslink polysaccharide chains
Penicillin mimics _____, the last 2 amino acids of the peptide-bridge precursor of peptidoglycan layer
Penicillin mimics D-Ala-D-Ala and is picked up by transpeptidase, but penicillin has beta-lactam ring at core (inhibits enzyme action)
[note that D refers to stereochemistry - D amino acids, which are only in bacteria, not humans - we only have L amino acids]
how do beta-lactamase proteins work to confer resistance to penicillins?
beta-lactamases act similarly to transpeptidases (target of penicillin), but hydrolyze serine-lactam linkage
hydrolyzed beta-lactam has no therapeutic value
beta-lactamases and transpeptidases belong to class of proteins that share ability to bind penicillins (PBPs - penicillin binding proteins)
how do beta-lactamase inhibitors work and how are they used?
do not have antibacterial activity - combined with beta-lactam antibiotics (penicillin) to extend their half-lives
inhibitors bind beta-lactamases covalently and inactive irreversibly
Avibactam
broad spectrum beta-lactamase inhibitor (does not contain beta-lactam core)
beta-lactamases have 3 classes: A, C, and D
Avibactam works on class A, C, and some D enzymes
what are the 3 classes of penicillin and a major example of each?
- common (penicillin G): acid labile, beta-lactamase susceptible
- anti-staphylococcal penicillin (cloxacillin): acid stable, beta-lactamase resistant
- extended-spectrum penicillins (amoxicillin): acid stable, inactivated by lactamases - require combination with lactamase inhibitors
CAP: cloxacillin, amoxicillin, penicillin
uses of cloxacillin vs amoxicillin vs penicillin G
penicillin G: Gram+/Gram- cocci and non-beta-lactamase producing anaerobes
cloxacillin (anti-staphylococcal): beta-lactamase-producing Staph and penicillin-susceptible strains of Strep. and pneumococci
amoxicillin (extended-spectrum): greater activity against Gram- bacteria (penetrate outer membrane)
what is cloxacillin, an anti-staphylococcal penicillin, suitable for? what is it not suitable for?
cloxacillin: acid stable, beta-lactamase resistant
suitable: beta-lactamase producing Staph, penicillin-susceptible strep. and pneumococci
NOT suitable: enterococci, anaerobic bacteria, Gram- cocci and rods
which of these types of penicillin have greater activity against Gram- bacteria?
a. penicillin G
b. cloxacillin
c. amoxicillin
c. amoxicillin: extended-spectrum penicillin, can penetrate outer membrane of Gram- bacteria
however, inactivated by lactamases, so require combination with beta-lactamase inhibitors (ex: amoxicillin + clavulanate = Augmentin)
provide the following for penicillins:
a. route of administration
b. route of elimination
c. adverse reactions
route of administration: oral, IV, IM
route of elimination: rapid active secretion via kidney —> use with probenecid which competitively inhibits secretion to increase steady state
adverse reactions: diarrhea, nausea, rash, urticaria (but very non-toxic), Candida superinfection
how can the steady state of penicillin be increased, given that it is rapidly secreted by the kidney?
take with probenecid which competitively inhibits secretion
take PRObenecid with Penicillin to PROactively extend its half life
by what mechanism does MRSA acquire penicillin resistance?
mutation in primary penicillin binding protein (PBP) - transpeptidase - which reduces affinity
name a first, second, third, and fourth generation cephalosporin (beta-lactam antibiotics)
1st: cefazolin: restricted to surgical prophylaxis, does not penetrate CNS
2nd: cefuroxime axetil
3rd: ceftriaxone: some cross BBB, no allergic cross-reactivity with penicillin, extend Gram- activity at expense of Gram+
4th: cefepime: true broad spectrum drug, penetrates CNS (also no cross-reactivity with penicillin), can be used for MRSA
when they played the Z[VI]OLIN I took my AXE and got in the X[Z]ONE and was at my P[R]IME
which of these cephalosporins is effective against inducible beta-lactamase-production but not constitutive beta-lactamase producing strains?
a. cefazolin
b. cefuroxime axetil
c. ceftriaxone
d. cefepime
c. ceftriaxone: 3rd gen, extends Gram- activity at expense of Gram+, some cross BBB, no allergic cross-reactivity with penicillin
which of these cephalosporins is restricted to surgical prophylaxis?
a. cefazolin
b. cefuroxime axetil
c. ceftriaxone
d. cefepime
a. cefazolin: 1st gen, broad spectrum but better for Gram+, does not penetrate CNS
which of these cephalosporins is a true broad spectrum drug that can penetrate the CNS?
a. cefazolin
b. cefuroxime axetil
c. ceftriaxone
d. cefepime
d. cefepime: 4th gen, more resistant to chromosomal beta-lactamases, no cross-reactivity with penicillin
for cephalosporins, provide the following:
a. route of administration
b. route of elimination
c. adverse reactions
route of administration: oral, IV
route of elimination: kidney
adverse reactions: hypersensitivity reactions (anaphylaxis, fever, rash, nephritis, granulocytopenia, hemolytic anemia), Candida superinfection
cefiderocol
beta-lactamase resistant cephalosporin with higher permeability to Gram- but no activity against Gram+
contains side chain that mimics bacterial siderophores (chelate iron to facilitate import) —> allows drug to enter like a trojan horse
administered via injection for complicated UTI
ceftaroline
cephalosporin with activity against MRSA
high/broad affinity towards transpeptidases, works on both Gram+ and Gram-
effective against skin infections, administered via IV
use of monobactams (such as aztreonam)
beta-lactam antibiotic, relatively resistant to beta-lactamases
great for Gram- rods, NO activity towards Gram+
given via IV and excreted rapidly, no cross-reactivity with penicillin
What are carbapenems and what are they used for?
beta-lactam antibiotics, broad spectrum, used for mixed infections
can penetrate CNS, renal clearance, given via IV
may be cross-sensitivity in patients with penicillin allergy
contrast Imipenem and Meropenem, two carbapenems (beta-lactam antibiotics, broad spectrum)
imipenem: inactivated by dehydropeptidases in renal tubules —> give with Cilastatin, an inhibitor of renal dehydropeptidases
meropenem: resistant to modification by renal dehydropeptidases
imipenem, a carbapenem (beta-lactam antibiotic), is inactivated by dehydropeptidases in renal tubules
what can be given with this drug to solve the issue?
Cilastatin: inhibitor of renal dehydropeptidases, increases half life of imipenem
what are 4 categories of beta-lactam cell wall synthesis inhibitor antibiotics?
- penicillins: penicillin G, cloxacillin, amoxicillin
- cephalosporins
- monobactams
- carbapenems
what is the structure of vancomycin like, and where does it bind? (non-beta-lactam cell wall synthesis inhibitor)
very large structure - limited to Gram+ bacteria
binds D-Ala-D-Ala chain and blocks BOTH transpeptidases and transglycosylases (creates steric block) —> bactericidal for actively growing cells
[remember that enterococci develops resistance by switching peptidoglycan to D-Ala-D-Lactate]
what is the advantage of dalbavancin and oritavancin, 2 semisynthetic cell wall synthesis inhibitors that can be used in place of vancomycin?
long half-life permits single dosing and outpatient care, whereas vancomycin requires 7-10 days by IV (expensive care for patients)
work by same mechanism as vancomycin (bind cell wall rather than enzymes used to make it)
daptomycin
non-beta-lactam cell wall synthesis inhibitor
large lipopetide (works on Gram+ only), causes pore formation that allows K+ release without cell rupture (so not toxin release!)
polymyxins
non-beta-lactam cell wall synthesis inhibitors
lipopeptides that are large but actually only work on Gram- bacteria —> bind LPS on outer membrane and cause perforations of both outer and inner membranes
[resistance can occur via changes in LPS structure]
what are 3 antibiotics that inhibit the assembly of peptidoglycan precursors within the bacterial cell? which steps do they inhibit?
- fosfomycin: inhibits first committed step (MurA enzyme, converts NAG-UDP to NAM-UDP)
- bacitracin: inhibits lipid phosphatase that works on carrier of peptidoglycan subunits
- D-cycloserine: competitively inhibits alanine racemase and D-alanine ligase
fosfomycin
antibiotic that inhibits assembly of peptidoglycan precursors within the cell, active against Gram+ and Gram-
inhibits first committed step: MurA enzyme converts NAG-UDP to NAM-UDP (covalently binds MurA)
[resistance via loss of drug transport into cell, and MurA of TB is naturally resistant]
bacitracin
antibiotic that inhibits assembly of peptidoglycan precursors within bacterial cell
inhibits lipid phosphatase that works on lipid carrier of peptidoglycan subunits
active against Gram+
D-cycloserine and its use
antibiotic that inhibits assembly of peptidoglycan precursors within bacterial cell wall
designed for TB treatment, otherwise not considered first-line because of serious side effects (CNS toxicity)
competitively inhibits alanine racemase and D-alanine ligase
what are 3 non-beta-lactam cell wall synthesis inhibitors?
- vancomycin: Gram+ only (large), blocks both transglycosylase and transpeptidase
- daptomycin: forms pores that allow K+ loss without cell rupture (no toxin release), Gram+ only
- polymyxins: lipopeptides that bind outer membrane of Gram- and create perforations
which of these cephalosporins contains a side chain that mimics bacterial siderophores?
a. ceftaroline
b. cefiderocol
c. ceftolozane
d. cefazolin
e. cefepime
b. cefiderocol: beta-lactamase resistant, highly permeability to Gram- (no Gram+ activity)
[remember that siderophores chelate iron to facilitate import]
ciFIDERocol mimics SIDEROphores
which of these cephalosporins is approved for use against MRSA?
a. cefiderocol
b. cefazolin
c. ceftriaxone
d. ceftaroline
d. ceftaroline: high/broad affinity towards transpeptidases, works on both Gram+ and Gram-
[remember that MRSA resistance is via mutation in transpeptidase]
Which of these beta-lactam antibiotics is inactivated by dehydropeptidases in renal tubules, and requires cilastatin (inhibitor of renal dehydropeptidases) to increase half life?
a. imipenem
b. aztreonam
c. ceftaroline
d. cloxacillin
a. imipenem: carbapenem, inactivated by dehydropeptidases
b. aztreonam: monobactam
c. ceftaroline: cephalosporin for MRSA
d. cloxacillin: anti-staphylococcal penicillin
which of these non-beta-lactam cell wall synthesis inhibitors forms pores in bacterial membrane that allow K+ loss without cell rupture, thus preventing toxin release?
a. oritavancin
b. dalbavancin
c. daptomycin
d. polymyxins
d. daptomycin: cyclic lipopeptide
which of these non-beta-lactam cell wall synthesis inhibitors is commonly used topically in form of triple antibiotic, such as neosporin?
a. daptomycin
b. polymyxins
c. vancomycin
b. polymyxins: lipopetides that bind LPS of Gram- bacteria and form perforations
which of these antibiotic inhibitors of peptidoglycan precursors assembly is used in combination therapy for TB, but second-line for all else due to CNS toxicity?
a. fosfomycin
b. bacitracin
c. D-cycloserine
c. D-cycloserine: competitively inhibits alanine racemase and D-alanine ligase
a. fosfomycin: inhibits MurA enzyme
b. bacitracin: inhibits lipid phosphatase
which of these antibiotics inhibiting assembly of peptidoglycan precursors works by inhibiting MurA enzyme?
a. fosfomycin
b. bacitracin
c. D-cycloserine
a. fosfomycin: inhibits first committed step in cell wall synthesis, in which MurA enzyme converts NAG-UDP to NAM-UDP (binds covalently)
b. bacitracin: inhibits lipid phosphatase
c. D-cycloserine: competitively inhibits alanine racemase and D-alanine ligase
which of these antibiotics inhibiting assembly of peptidoglycan precursors works by inhibiting a lipid phosphatase?
a. fosfomycin
b. bacitracin
c. D-cycloserine
b. bacitracin: inhibits lipid phosphatase that dephosphorylates lipid carrier of peptidoglycan subunits (only used topically because it is nephrotoxic)
a. fosfomycin: inhibits MurA enzyme
c. D-cycloserine: competitively inhibits alanine racemase and D-alanine ligase
