Gartenberg - Cell Wall Actibiotics Flashcards

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1
Q

If someone comes in with a serious bacterial infection what should you do?

A

1) GIve a broad spectrum antibiotic or utilize combination therapy
2) Grow a culture and figure out which organism is responsible for the infection.
3) Once identified, treat with a narrow-spectrum drug.

  • keep in mind, Bacteriostatic drugs may inhibit the action of Bacteriostatic drugs that rely on active cell growth.
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2
Q

why is it that cell wall antibiotics often don’t work as well on Gram - bacteria?

A

Because the gram - bacteria have a outer cell wall layer, they have difficulty getting access to the cell wall.

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3
Q

Broad spectrum

A

Drugs that work against both gram+ and gram-

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4
Q

Extended spectrum

A

A drug whose selectivity is broadened by chemical modification

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5
Q

What types of molecules are best for treatment of gram - bacteria?

A

Small hydrophilic molecules that can fit through their transmembrane pores.

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6
Q

What other factors dictate specificity once inside of the cell?

A

Affinity of the drug for their target

Ability of drugs to evade systems that eliminate them (efflux pumps)

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7
Q

General structure of cell wall

A

NAG and NAM come together as one monomeric unit. They combine with other moomeric units by transglycosylases outside of the cell. Then in order to cross link a second polysaccharide we use transpeptidases.
- The peptides contain two D-Alas that are connected by Gylcines in the middle only in G+ (5 glycines).

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8
Q

Transglycosylase

Transpeptidase

A

Transglycosylase - join monomeric sugars of NAG/NAM to other monomeric sugars outside of the cell in order to create a polysaccharide.

Transpeptidase - joins the polysaccharides together to cross link them.

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9
Q

What are some common beta-lactam drugs?

A

Penicillin

Cephalosporin

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10
Q

WHat is the biochemical mechanism of action of transpeptidases?

A

They have a serine group in their active site. The serine attacks the peptide bond between the two D-Alas. This causes one D-Ala to leave as a leaving group. Then, a glycine from a second polysaccharide comes in and attacks the D-Ala and covalently bonds to it while the transpeptidase is a leaving group.

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11
Q

Mechanism of action of Penicllin And the beta-lactam class of drugs?

A

Penicllin looks a whole lot like the D-Ala D-Ala moiety. Therefore, the serine residue of the transpeptidase attacks Penicllin instead of the actively growing cell wall. Penicllin is actually larger than the D-Ala D-Ala within the active site, so there is no room for Glycine or H2O to come in and release Penicllin.

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12
Q

What was the bacterias response to beta-lactam drugs?

A

Beta-lactamases

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13
Q

What did microbes do in order to protect themselves from beta-lactams?

A

They began secreting beta-lactamases. These enzymes look like transpeptidases and they bind to the Penicllin, but these beta-lactamases have much larger active sites than does transpeptidases, so H2O is able to come in and hydrolyze the bond and release the penicillin but not in the original structure.

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14
Q

What did the pharmaceutical industry do to combat the activity of beta-lactamases?

A

Beta-lactamase inhibitors

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15
Q

What is an example of Beta-lactamase inhibitors?

A

Clavulanic acid

Avibactum

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16
Q

How do beta-lactamase inhibitors work?

A

They are similar to penicillin but much larger. So they bind to the beta-lactamases and irreversibly inactivate them.
- they have no intrinsic antibacterial activity, they are just given with beta-lactam antibiotics like penicillin in order to increase their half-life and ability to do their job.

17
Q

Why is Avibactam different than the other beta-lactamase inhibitors?

A

Because usually beta lactamases have three classes - A, B, and D. Most beta-lactamases inhibitors work on class A enzymes. Avibactam works on class A, C, and D - it is broader spectrum.

18
Q

What was the progression of penicillins and what added benefit did they each have?

A

Penicllin G - this was the original. It is acid Labile so a lot of it would get destroyed in the stomach. It would be inactivated by beta-lactamases though.

Oxacillin, cloxacillin, dicloxacillin - acid stable so it would make it though the harsh environment of the stomach. It is resistant to beta-lactamases.

Amoxicillin - acid stable. It has enhances specificity against gram - because it could penetrate the outer membranes.
- often couples with a beta-lactamase inhibitor (Augmentin)

19
Q

What is Augmentin?

A

Combination of amoxicillin and clavulanate

- extended-spectrum Penicllin and a beta-lactamase inhibitor.

20
Q

Probenecid

A

Competitively inhibits secretion of Penicllin to increase its half life. Otherwise it is often excreted in 3-4 hours.

21
Q

Cephalosporins

A
Have increased resistance to beta-lactamases. 
- this class of drug starts with "cef"
22
Q

Progression of cephalosporin with each generation

A

1 - broad spectrum. Only really used for prophylactic surgery. Doesn’t penetrate CNS

2 - broad spectrum but increased coverage of G- bacteria. No allergic cross-reactivity with penicillin

3 - extend G- activity even further at the expense of G+. Somewhat crosses the blood-brain barrier.
- When combined with a beta-lactamase inhibitor it is called Avycaz

4 - increased activity. Against G+ and G-. Can cross CNS.

23
Q

What do you have to worry about when giving a cephalosporin?

A

Renal insufficiency because it is excreted through the kidney. It can cause seizures in these patients.

24
Q

What is the name of the 5th generation cephalosporin and what’s its deal?

A

ceftolozane
- often coupled with tazobactam (beta-lactamases inhibitor) to make a drug called Zerbaxa
- often used in case where microbe became resistant to other drugs - good against pseudomonas
-

25
Q

Ceftaroline

A

One of the cephalosporins that actively acts on transpeptidases unique to MRSA

26
Q

Monobactams

A

Looks like a beta-lactam but only has one ring.

  • Because of this it is very active against G- microbes, specifically rods.
  • aztreonam
27
Q

Carbapenems

- imbipenem

A

Broad spectrum antibiotic used to treat mixed infections.

  • Resistant against beta-lactamases
  • can be cleared by dehydropeptidases in renal tubules, which is why we give cilastatin, which is an inhibitor or dehydropeptidases
28
Q

Vancomycin

A

Very large so it can’t act on Gram -, it is used exclusively against G+, specifically staphylococci.

  • it binds to the growing polysaccharide chain and doesn’t allow for the transpeptidase or transglycosylase to get to it.
  • This causes lysis of the growing cell.
  • resistant to strains of enterococci that switch from D-Ala and D-Ala to D-Ala and D-Lac
29
Q

what are some of the new types of vancomycin and why are they better?

A

Dalbavancin and oritavancin (“vancin”

- less frequent dosing - vanco needs to be given via IV for 7-10 days.

30
Q

Daptomycin

A

Causes pores in the cell, which are large enough for K+ to leak out. Cell does not rupture though so you don’t have to worry about toxins.
- Used for G+.

31
Q

Polymixins

A

a very large lipopeptide that works on G- cells.

  • they split open the G- cell walls to allow it to be active to other drugs.
  • commonly used in neosporin
32
Q

Fosfomycin

A

Drug inhibits the first committed in cell wall synthesis, the conversion of NAG-UDP to NAM-UDP.

  • it does this by binding to the active site of the MurA enzyme
  • TB is naturally resistant.
33
Q

Bacitracin

A

inhibit lipid phosphatase that dephosphorylates lipid carrier of peptidoglycan subunits.

  • Used against G+
  • nephrotoxic so only used topically
34
Q

D-cycloserine

A

Produced by soil bacteria, it is structurally related to D-Ala. It competitively inhibits alanine racemase and D-Ala ligase.
- second line treatment for TB, but only used for that indication due to severe CNS toxicity.