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Foundations Exam 3 > Antibiotics Against Cell Wall Synthesis > Flashcards

Antibiotics Against Cell Wall Synthesis Flashcards

1
Q

broad spectrum vs extended spectrum

A

broad spectrum: work against both Gram+ and Gram- bacteria

extended spectrum: selectivity is broadened by chemical modification

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2
Q

why don’t larger drugs typically work on Gram- bacteria?

A

outer lipid membrane of Gram- bacteria is relatively impervious - transport of drugs through transmembrane pores favores small hydrophilic drugs

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3
Q

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

A

Transglycosylase enzymes join the sugars that make polysaccharide chains
and
Transpeptidase enzymes join the sugar-linked peptides to crosslink polysaccharide chains

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4
Q

Penicillin mimics _____, the last 2 amino acids of the peptide-bridge precursor of peptidoglycan layer

A

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]

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5
Q

how do beta-lactamase proteins work to confer resistance to penicillins?

A

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)

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6
Q

how do beta-lactamase inhibitors work and how are they used?

A

do not have antibacterial activity - combined with beta-lactam antibiotics (penicillin) to extend their half-lives

inhibitors bind beta-lactamases covalently and inactive irreversibly

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7
Q

Avibactam

A

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

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8
Q

what are the 3 classes of penicillin and a major example of each?

A
  1. common (penicillin G): acid labile, beta-lactamase susceptible
  2. anti-staphylococcal penicillin (cloxacillin): acid stable, beta-lactamase resistant
  3. extended-spectrum penicillins (amoxicillin): acid stable, inactivated by lactamases - require combination with lactamase inhibitors

CAP: cloxacillin, amoxicillin, penicillin

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9
Q

uses of cloxacillin vs amoxicillin vs penicillin G

A

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)

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10
Q

what is cloxacillin, an anti-staphylococcal penicillin, suitable for? what is it not suitable for?

A

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

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11
Q

which of these types of penicillin have greater activity against Gram- bacteria?
a. penicillin G
b. cloxacillin
c. amoxicillin

A

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)

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12
Q

provide the following for penicillins:
a. route of administration
b. route of elimination
c. adverse reactions

A

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

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13
Q

how can the steady state of penicillin be increased, given that it is rapidly secreted by the kidney?

A

take with probenecid which competitively inhibits secretion

take PRObenecid with Penicillin to PROactively extend its half life

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14
Q

by what mechanism does MRSA acquire penicillin resistance?

A

mutation in primary penicillin binding protein (PBP) - transpeptidase - which reduces affinity

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15
Q

name a first, second, third, and fourth generation cephalosporin (beta-lactam antibiotics)

A

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

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16
Q

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

A

c. ceftriaxone: 3rd gen, extends Gram- activity at expense of Gram+, some cross BBB, no allergic cross-reactivity with penicillin

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17
Q

which of these cephalosporins is restricted to surgical prophylaxis?
a. cefazolin
b. cefuroxime axetil
c. ceftriaxone
d. cefepime

A

a. cefazolin: 1st gen, broad spectrum but better for Gram+, does not penetrate CNS

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18
Q

which of these cephalosporins is a true broad spectrum drug that can penetrate the CNS?
a. cefazolin
b. cefuroxime axetil
c. ceftriaxone
d. cefepime

A

d. cefepime: 4th gen, more resistant to chromosomal beta-lactamases, no cross-reactivity with penicillin

19
Q

for cephalosporins, provide the following:
a. route of administration
b. route of elimination
c. adverse reactions

A

route of administration: oral, IV

route of elimination: kidney

adverse reactions: hypersensitivity reactions (anaphylaxis, fever, rash, nephritis, granulocytopenia, hemolytic anemia), Candida superinfection

20
Q

cefiderocol

A

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

21
Q

ceftaroline

A

cephalosporin with activity against MRSA

high/broad affinity towards transpeptidases, works on both Gram+ and Gram-

effective against skin infections, administered via IV

22
Q

use of monobactams (such as aztreonam)

A

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

23
Q

What are carbapenems and what are they used for?

A

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

24
Q

contrast Imipenem and Meropenem, two carbapenems (beta-lactam antibiotics, broad spectrum)

A

imipenem: inactivated by dehydropeptidases in renal tubules —> give with Cilastatin, an inhibitor of renal dehydropeptidases

meropenem: resistant to modification by renal dehydropeptidases

25
Q

imipenem, a carbapenem (beta-lactam antibiotic), is inactivated by dehydropeptidases in renal tubules

what can be given with this drug to solve the issue?

A

Cilastatin: inhibitor of renal dehydropeptidases, increases half life of imipenem

26
Q

what are 4 categories of beta-lactam cell wall synthesis inhibitor antibiotics?

A
  1. penicillins: penicillin G, cloxacillin, amoxicillin
  2. cephalosporins
  3. monobactams
  4. carbapenems
27
Q

what is the structure of vancomycin like, and where does it bind? (non-beta-lactam cell wall synthesis inhibitor)

A

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]

28
Q

what is the advantage of dalbavancin and oritavancin, 2 semisynthetic cell wall synthesis inhibitors that can be used in place of vancomycin?

A

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)

29
Q

daptomycin

A

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!)

30
Q

polymyxins

A

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]

31
Q

what are 3 antibiotics that inhibit the assembly of peptidoglycan precursors within the bacterial cell? which steps do they inhibit?

A
  1. fosfomycin: inhibits first committed step (MurA enzyme, converts NAG-UDP to NAM-UDP)
  2. bacitracin: inhibits lipid phosphatase that works on carrier of peptidoglycan subunits
  3. D-cycloserine: competitively inhibits alanine racemase and D-alanine ligase
32
Q

fosfomycin

A

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]

33
Q

bacitracin

A

antibiotic that inhibits assembly of peptidoglycan precursors within bacterial cell

inhibits lipid phosphatase that works on lipid carrier of peptidoglycan subunits

active against Gram+

34
Q

D-cycloserine and its use

A

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

35
Q

what are 3 non-beta-lactam cell wall synthesis inhibitors?

A
  1. vancomycin: Gram+ only (large), blocks both transglycosylase and transpeptidase
  2. daptomycin: forms pores that allow K+ loss without cell rupture (no toxin release), Gram+ only
  3. polymyxins: lipopeptides that bind outer membrane of Gram- and create perforations
36
Q

which of these cephalosporins contains a side chain that mimics bacterial siderophores?
a. ceftaroline
b. cefiderocol
c. ceftolozane
d. cefazolin
e. cefepime

A

b. cefiderocol: beta-lactamase resistant, highly permeability to Gram- (no Gram+ activity)

[remember that siderophores chelate iron to facilitate import]

ciFIDERocol mimics SIDEROphores

37
Q

which of these cephalosporins is approved for use against MRSA?
a. cefiderocol
b. cefazolin
c. ceftriaxone
d. ceftaroline

A

d. ceftaroline: high/broad affinity towards transpeptidases, works on both Gram+ and Gram-

[remember that MRSA resistance is via mutation in transpeptidase]

38
Q

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

a. imipenem: carbapenem, inactivated by dehydropeptidases

b. aztreonam: monobactam
c. ceftaroline: cephalosporin for MRSA
d. cloxacillin: anti-staphylococcal penicillin

39
Q

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

A

d. daptomycin: cyclic lipopeptide

40
Q

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

A

b. polymyxins: lipopetides that bind LPS of Gram- bacteria and form perforations

41
Q

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

A

c. D-cycloserine: competitively inhibits alanine racemase and D-alanine ligase

a. fosfomycin: inhibits MurA enzyme
b. bacitracin: inhibits lipid phosphatase

42
Q

which of these antibiotics inhibiting assembly of peptidoglycan precursors works by inhibiting MurA enzyme?
a. fosfomycin
b. bacitracin
c. D-cycloserine

A

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

43
Q

which of these antibiotics inhibiting assembly of peptidoglycan precursors works by inhibiting a lipid phosphatase?
a. fosfomycin
b. bacitracin
c. D-cycloserine

A

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

Foundations Exam 3 (28 decks)

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