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5224 > Cell Wall Synthesis Inhibitors I > Flashcards

Cell Wall Synthesis Inhibitors I Flashcards

1
Q

Who isolated penicillin

A

Alexander Fleming in 1928

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2
Q

When was penicillin used clinically

A

1940’s

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3
Q

What are the B-lactam abx?

A
  • Penicillins
  • Cephalosporins
  • Carbapenems
  • Monobactams
    (same MOA for all of the above)
  • B-lactamase inhibitors (assist B-lactams)
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4
Q

What do all penicillins have in common

A
  • B-lactam ring with amide group
  • Thiazolidine ring with two methyl groups and a carboxyl group
  • Differ in R-side chain
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5
Q

Where is the R-side chain attached

A

to the B-lactam ring via the amide group

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6
Q

What is the critical component of penicillins

A
  • the B-lactam ring

- also found in other subclasses of CWSI

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7
Q

MOA of B-lactams

A
  • interfere with peptidoglycan synthesis in BOTH Gram + an Gram -
  • Bind to transpeptidases to inhibit cross-linking = cannot form stable cell wall
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8
Q

What do transpeptidases do

A

perform the final step of peptidoglycan crosslinking

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9
Q

What are Penicillin Binding Proteins? (PBPs)

A

another name for transpeptidase. They bind to penicillin, hence the name

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10
Q

How is the bacterial cell wall built

A
  • consists of peptidoglycan, which is made of polysaccharides that are cross-linked via small peptides.
    Gram - have a few layers
    Gram + have several layers
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11
Q

Which bacteria has an outer membrane

A

Gram -

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12
Q

Final step of peptidoglycan synthesis

A
  • crosslinking of precursor molecules consisting of separate strands with peptides, attached via the peptides
  • process catalyzed by transpeptidases
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13
Q

What do transpeptidases recognize

A
  • terminal D-Ala-D-Ala of a peptide
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14
Q

Is transpeptidase preserved during peptidogylcan synthesis

A

yes

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15
Q

Are B-lactams reversible or irreversible inhibitors of transpeptidase

A

irreversible

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16
Q

What do B-lactams mimic

A
  • the D-Ala-D-Ala portion of the peptide and acylate transpeptidase instead
  • amide bonds mimics the peptide bond btwn the two D-Ala
  • transpeptidase binds the B-lactam instead and is irreversibly inhibited
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17
Q

What is the result of transpeptidase binding a B-lactam

A

cell walls cannot grow or repair anymore. Cell loses shape, leads to lysis, and cell death

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18
Q

is resistance to B-lactams common or uncommon

A
  • resistance is common
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19
Q

General resistance mechanism: Mutate or protect the target and make it insensitive to the abx. How is this specific to B-lactams

A
  • bacterial mutation of transpeptidase to decrease affinity for B-lactams
20
Q

General resistance mech: Decrease access of abx to target. How is this specific to B-lactams

A
  • decreased permeability of cell envelope.

- Active transport of abx out of cell via efflux pumps

21
Q

General resistance mech: Inactivate Abx. How is this specific to B-lactams

A
  • Hydrolysis of B-lactam ring by B-lactamase (MOST COMMON MECHANISM)
22
Q

General resistance mech: Replace the target with another molecule that can do the same job (alternate biochem pathway). How is this specific in B-lactams

A
  • Express an alternative, low-affinity transpeptidase (intrinsic or acquired). E.g. very common in MRSA
23
Q

How are B-lactamases classified

A
  • four classes based on sequence homology
  • A, C, and D are serine enzymes
  • B are metalloenzymes containing Zn(II)
  • serine enzymes are related to PBP’s
24
Q

How are B-lactamases named

A
  • according to their substrate preference
  • penicillinases bind penicillin
  • cephalosporinases bind cephalosporin
  • carbapenemases bind carbapenem
25
Q

Classification of penicillins

A
  • all have the same core, called penam

- all have same MOA (inhibition of transpeptidase by acylation)

26
Q

What is the penam core composed of

A

fused B-lactam and thiazolidine rings

27
Q

What does identity of R group determine

A
  • antimicrobial activity
  • absorption
  • acid stability (drug shouldn’t break down before absorbed)
  • stability to B-lactamases (make R group bulky to resist)
28
Q

Most common adverse effect of penicillin (and cephalosporins and carbapenems)

A

hypersensitivity reaction

29
Q

How are R-groups introduced

A
  • fermentation

- semisynthtically

30
Q

Penicillin V (VK for potassium)

A
  • broad spectrum (Gram + and Gram -)
  • 90% of staph aureus in hospitals is resistant
  • rapidly absorbed
  • widely distributed
  • no CSF penetration
  • rapidly excreted unchanged (problem for resistance)
31
Q

Penicillinase-resistant penicillins

A
  • resistant to hydrolysis and inactivation by staphylococcal penicillinase
  • Methicillin, Isoxazolyl penicillins, Nafcillin
  • enzymes can now inactivate these as well
32
Q

Isoxazolyl penicillins

A
  • acid stable and well absorbed
  • used against penicillinase-producing staph
  • NOT useful to Gram - bacteria
  • Penicillinase-resistant penicillins
33
Q

Nafcillin

A
  • irregular oral absorption (inject)
  • highly resistant to staph penicillinases
  • Good BBB penetration = can treat meningitis
  • Penicillinase-resistant penicillins
34
Q

Aminopenicillins

A
  • KNOW augmentin
  • Gram + and Gram -
  • More broad spectrum
  • Useful against menigococci and listeria
  • rapidly inactivated by B-lactamase
  • can recover activity by adding B-lactamase inhibitor
35
Q

What is augmentin

A

Amoxicillin + clavulanic acid
Aminopenicillin
- R = H

36
Q

Uses of aminopenicillins

A
  • upper respiratory infections
  • middle ear infections
  • UTI
  • meningitis (in combo with Vancomycin and 3rd gen cephalosporin)
  • salmonella
37
Q

Amoxicillin

A
  • aminopenicillin
  • R = OH
  • BBB penetration
  • rapidly inactivated (see augmentin)
38
Q

Carboxypenicillins

A
  • active against pseudomonas and proteus spp that are resistant to ampicillin
  • INeffective against staph, enterococcus, Klebsiella, and Listeria
  • inactivated by B-lactamases
39
Q

Ureidopenicillins: piperacillin

A
  • covers most strains of pseudomonas, non-B-lactamase producing Enterobaceriacea, etc
  • Broadest spectrum of all penicillins when in combo with B-lactamase inhibitor
  • used against serious Gram - infections (often nosocomial)
40
Q

What is zosyn

A

piperacillin + tazobactam

41
Q

why do penicillins produce hypersensitivity

A
  • look like small peptides
42
Q

B-lactamase inhibitors

A
  • technically B-lactams but have very weak antibacterial action (no R-group)
  • POTENT inhibitors of many (NOT ALL) B-lactamases
  • give with abx to restore antibacterial properties
43
Q

Three B-lactamase inhibitors

A
  • clavulanic acid
  • sulbactam
  • tazobactam
44
Q

How are B-lactamases available? (in what form)

A
  • only in combo with penicillins and cephalosporins

- KNOW: augmentin (amoxicillin-clavulanate)

45
Q

B-lactamase MOA

A
  • acylate serine B-lactamases, five-membered ring opens up and forms second covalent bond with the enzyme.
  • gets stuck in enzyme, irreversibly inhibiting it

5224 (9 decks)

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