Bacterial Cell Wall and Beta Lactam Antibiotics - Cushman #1

Describe the differece in drug penetration between gram positve and gram negative

in gram positive, drugs can penetrate the outer laters effectively with the bacterial membrane being the main barrier keeping drugs out. In gram negative, the outer membrane excludes drugs but some can enter through porins

Compare the number of membranes between a Gram pos and Gram neg bacteria

Gram pos has 1 membrane and gram neg has 2 membranes, an inner and outer, making it more lipoidal

Gram positive has____ cell walls while Gram neg has ____ cell walls. Thick vs thin

Gram positive has thick cell walls while gram negative has thin cell walls

Describe Gram Positive bacteria peptidoglycan content and its bridging

contains meso-DAP. Crosslink between DAP and D-Ala

Describe Gram Negative bacteria peptidoglycan content and its bridging

Instead of DAP, it has L-Lys. Crosslink between L-lys and D-Ala

MOA of b-lactam antibiotics

B-lactam antibiotics acylate the transpeptidase Ser residue which inactivates the enzymes and inhibits crosslinking. This causes a defective cell wall which makes it subject to osmotic lysis and cell death

What part of the transpeptidase has high reactivity?

the 4 membered ring

How does a b-lactam antibiotic allergy (penicillin allergy) come about?

Penicillin acts as a hapten and it acylates the host cell proteins. This raises antibodies which resutls in an allergic reaction

In terms of serum protein binding, drugs that are more lipophilic are what? What does this cause mean for the drug?

more highly protein binding which means the drug is less effective

Use of this drug increases the half life of penicillin which allows for penicillin to fight bacteria for longer

probenecid

What happens to the half life of penicillin in cases of kidney disease or failure?

increases

How much penicilin is renally excreted by glomerular filtration

10%

How much penicilin is renally excreted by tubular filtration

90%

Benzylpenicillin (Penicillin G)

1) Antimicrobial spectrum

2) Is it B-lactamase sensitive?

3) Route of Admin

4) Toxicity

5) Precautions

1) Gram pos cocci 2) yes 3) parenteral 4) acute allergic reactions 5) caution in pts with history of significant allergies and/or asthma

Between Penicillin G and Penicillin V, which is more stable in acidic conditions? Why?

Penicillin V is more stable in acid because it has an electronegativ ether oxygen, making it less nucleophilic which decreases suspectibility to hydrolysis

Methicillin

1) Antimicrobial spectrum

2) Is it B-lactamase sensitive?

3) Why? ^

4) Route of Admin

Gram positvie. It is not sensitive to B-lactamase due to the steric hinderance of the nucleophilic attack on the enzyme by on the b-lactam carbonyl. Parenteral

Methicillin is ineffective against what?

Ineffective against MRSA due to PBP (transpeptidase) mutation. The mutation has a gene code of mecA.mecA + PBP2A = MRSA

What are the oral options that are B-lactamase resistant? What is significant about their structure and explain briefly in laymans terms? Are they all still used and if so, how?

Oxacillin, Cloxacillin, and dicloxacillin. They are are isoxazoles which means they have 5 membered ring with an adjacent O and N. Oxacillin and cloxacillin are d/c orally but dicloxacillin is still used orally. Oxacillin still available by injection

Broad Spectrum, B-Lactamase Sensitive, Oral Penicillins

1) What are the drugs

2) Which has better absorption and why?

3) What about both their structures allows for it to be taken orally and for it to be broad-spectrum?

Ampicillin and Amoxicillin. Amoxicilin has better absorption due to its phenolic hydroxyl group. They have a charged amino group that allows for the drug to to be transported into the gram negative through the porins

Broad Spectrum, B-Lactamase Sensitive, Oral Penicillins like Ampicillin and Amoxicillin can be used for what bacterias?

Salmonella. Shegella, proteus mirabilis, E.coli

What are examples of B-lactamase inhibitors?

Clavulanic acid, Sulbactam, Tazobactam, and Avibactam

What do b-lactamase inhibitors do?

Enhance activity of b-lactamase sensitve b-lactams

Broad Spectrum, B-lactamase sensitive, parenteral penicillin

1) Example

2) Structural Significance

3) Active against what notable bacteria

Piperacillin. Contains urea moiety and has a longer peptidoglycan fragment which makes it broad spectrum and enhances potency. It is active against Pseudomonas, Klebsiella, and bacteroides

Explain the MOA of cephalosporins

Same as pencillin where they react with transpeptidase (PBPs) and inhibit peptidoglycan crosslinking which causes a defective bacteria cell wall causing osmotic lysis and cell death

How does something become resistant to cephalosporins

Hydrolysis by b-lactamases

What is the trend for cephalosporins 1st gen to 3rd gen

Increased Gram negative activtiy and decreased gram positive activity

Orally active 1st gen cephalosporins have what in their structure that makes it orally active?

unreactive side chains at C-3, methyl group for 1st gen

2nd Gen cephalosporin

1) example

2) antimicrobial spectrum

3) structural significance

Cefuroxime has gram positive activity as well as activtiy againsts Haemophilis influenza. It has some activity against gram negative. These have carbamate side chains that neutralize the partial postive charge, making it less nucleophilic, and enchancing oral bioavailabilty. Some have oxime ether that help with resistance agains hydrolysis and the syn formation is more resistance against hydrolysis

3rd Gen cephalosporin

1) example

2) antimicrobial spectrum

3) structural significance + oral or parenteral?

Ceftazidime, Cefixime, Cefepime are mainly active against gram neg bacteria including nosocomial bacteria. They have an aminothiazole substituent, a large oxime ether which increases stability, and a charged pyridinium ring that enhances aqueous solubility, making it parenterally active

4th Gen cephalosporin

1) example

2) antimicrobial spectrum

3) Structural significance + how it’s used

Cefepime. Gram neg and gram pos. Has a syn methoximo group that increases stability. Has N-methylpyrrolidine (charged N) which make it a good leaving group so it is used parenterally

Cephalosporins with what are more likely to be active against Gram neg bacteria

positively charged nitrogen