Gartenberg - Cell Wall Actibiotics Flashcards
(34 cards)
If someone comes in with a serious bacterial infection what should you do?
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.
why is it that cell wall antibiotics often don’t work as well on Gram - bacteria?
Because the gram - bacteria have a outer cell wall layer, they have difficulty getting access to the cell wall.
Broad spectrum
Drugs that work against both gram+ and gram-
Extended spectrum
A drug whose selectivity is broadened by chemical modification
What types of molecules are best for treatment of gram - bacteria?
Small hydrophilic molecules that can fit through their transmembrane pores.
What other factors dictate specificity once inside of the cell?
Affinity of the drug for their target
Ability of drugs to evade systems that eliminate them (efflux pumps)
General structure of cell wall
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).
Transglycosylase
Transpeptidase
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.
What are some common beta-lactam drugs?
Penicillin
Cephalosporin
WHat is the biochemical mechanism of action of transpeptidases?
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.
Mechanism of action of Penicllin And the beta-lactam class of drugs?
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.
What was the bacterias response to beta-lactam drugs?
Beta-lactamases
What did microbes do in order to protect themselves from beta-lactams?
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.
What did the pharmaceutical industry do to combat the activity of beta-lactamases?
Beta-lactamase inhibitors
What is an example of Beta-lactamase inhibitors?
Clavulanic acid
Avibactum
How do beta-lactamase inhibitors work?
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.
Why is Avibactam different than the other beta-lactamase inhibitors?
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.
What was the progression of penicillins and what added benefit did they each have?
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)
What is Augmentin?
Combination of amoxicillin and clavulanate
- extended-spectrum Penicllin and a beta-lactamase inhibitor.
Probenecid
Competitively inhibits secretion of Penicllin to increase its half life. Otherwise it is often excreted in 3-4 hours.
Cephalosporins
Have increased resistance to beta-lactamases. - this class of drug starts with "cef"
Progression of cephalosporin with each generation
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.
What do you have to worry about when giving a cephalosporin?
Renal insufficiency because it is excreted through the kidney. It can cause seizures in these patients.
What is the name of the 5th generation cephalosporin and what’s its deal?
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
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