Penicillin Flashcards
What are the differences between Gram-(+) and Gram-(–) bacteria regarding drug penetration?
Gram-(+): Drugs can penetrate the outer layers of the cell wall effectively.
Gram-(–): The outer membrane excludes drugs, but some drugs still get through the porins.
How is the distribution of beta-lactamases different in Gram-(+) and Gram-(–) bacteria?
Gram-(+): Beta-lactamases are excreted through the cell wall to the external environment; they must be produced in larger quantities.
Gram-(–): Beta-lactamases are confined to the periplasmic space.
What is the peptidoglycan thickness in Gram-(+) and Gram-(–) bacteria?
Gram-(+): Thick peptidoglycan.
Gram-(–): Thin peptidoglycan.
How many membranes are present in the cell wall of Gram-(+) and Gram-(–) bacteria?
Gram-(+): One bacterial membrane.
Gram-(–): Two membranes - outer membrane and inner membrane.
What is the peptidoglycan content in Gram-(+) and Gram-(–) bacteria?
Gram-(+): the DAP residue is replaced by an L-lysine residue (COOH of DAP is replaced by an H)
Gram-(–): the peptidoglycan contains a meso-diaminopimelic acid residue (DAP)
How does peptidoglycan bridging differ in Gram-(+) and Gram-(–) bacteria?
Gram-(+): The bridge exists between the L-Lys strand and the terminal D-Ala of the second molecule.
Gram-(–): Peptidoglycan is cross-linked by a bridge between the DAP residue of one strand and the terminal D-Ala of another.
What is the role of transpeptidase in bacterial cell wall strength?
Transpeptidase cross-links peptidoglycan strands, which is necessary to confer strength to the bacterial cell wall to prevent lysis.
How does transpeptidase function in cross-linking peptidoglycan?
Transpeptidase has a serine residue in its active site that carries out a nucleophilic attack on the amide carbonyl, forming a tetrahedral intermediate and linking peptidoglycan strands.
What is the mechanism of action of penicillins?
Penicillin is a beta lactam-antibiotic; beta-lactam MOA: Penicillin inhibits transpeptidases that glue peptidoglycan strands together by cross-linking, inhibiting bacterial cell wall synthesis, which kills the bacteria.
How do beta-lactam antibiotics inactivate transpeptidase?
Beta-lactam antibiotics acylate the transpeptidase Ser residue, forming a stable product that inhibits peptidoglycan cross-linking, leading to cell lysis and death.
What structural feature of beta-lactams allows them to mimic D-Ala-D-Ala?
The structures of beta-lactams resemble the D-Ala-D-Ala fragment, allowing them to ‘fool’ transpeptidase into thinking they are the D-Ala-D-Ala fragment.
What are common bacterial resistance mechanisms toward penicillins?
Resistance may result from decreased drug uptake, mutations in penicillin-binding proteins, or the presence of efflux pumps. A common mechanism is the induction of beta-lactamases that hydrolyze the beta-lactam moiety. The beta-lactamases form hydrolyzed penicillin (penicillin that is broken down, so it’s inactive as an antibiotic)
How does penicillin allergenicity occur?
Beta-lactam antibiotics act as haptens, acylating host cell proteins and raising antibodies that lead to allergic reactions.
What happens to penicillins under acidic conditions?
Under acidic conditions, Pen G degrades to benzylpenicillenic acid, benzylpenillic acid, and benzylpenicilloic acid, making it unstable for oral administration.
What happens to penicillins under basic conditions?
hydroxyl group attacks carbonyl to form a penicilloic acid.
What is the main chemical feature of penicillins that confers resistance to acidic degradation?
The presence of a phenoxymethyl group attached to the beta-lactam ring in penicillin V provides resistance to degradation under acidic conditions, allowing it to be taken orally. This modification stabilizes the molecule against hydrolysis in acidic environments. So, pen V is more stable to hydrolysis in the stomach than pen G because the electronegativity of the ether oxygen decreases the nucleophilicity of the amide carbonyl
What conditions promote penicillin degradation?
Heavy metal ions catalyze penicillin degradation reactions.
How does lipophilicity of penicillins affect their serum protein binding?
As CLogP increases, it is more lipophilic. Penicillins with more lipophilic side chains are more highly protein bound.
How does penicillin serum protein binding affect bioavailability?
Protein binding reduces bioavailability by reducing the effective concentration of the free drug.
What are the mechanisms of penicillin excretion?
Penicillins are rapidly excreted by the renal or biliary routes. For those excreted by kidneys, 10% is by glomerular filtration and 90% is by tubular secretion.
How does renal disease affect penicillin half-life?
The half-lives of penicillins that are excreted by the kidneys are prolonged in cases of kidney disease or failure.
How does probenecid affect penicillin half-life?
Probenecid competes with penicillin for tubular secretion, causing an increase in half-life when administered together.
What chemical features stabilize penicillins against hydrolysis by b-lactamases?
Bulky, branched side chains at the C-6 position of their core structure stabilize penicillins against hydrolysis by beta-lactamases.
What is penicillin G also known as?
Benzylpenicillin.
What is the antimicrobial spectrum of penicillin G?
It is effective against gram-(+) cocci; therapy should be guided by susceptibility testing.
Is penicillin G sensitive to beta-lactamases?
Yes, it is easily broken down and rendered ineffective by the enzyme beta-lactamase.
How is penicillin G administered?
It is administered parenterally.
What are the toxicity concerns associated with penicillin G?
Acute allergic reactions.
What precautions should be taken when using penicillin G?
Use caution in patients with histories of significant allergies and/or asthma.
What is the main difference between phenoxymethyl penicillin (penicillin V) and penicillin G?
Penicillin V is more stable in acid and can be given orally.
What chemical feature contributes to the stability of penicillin V in acid?
The electronegative ether oxygen decreases the nucleophilicity of the side chain amide carbonyl. This therefore decreases its participation in the beta-lactamase hydrolysis reaction
Classify the major penicillins based on their resistance to beta-lactamases.
Beta-lactamase-resistant parenteral penicillins: methicillin, nafcillin; beta-lactamase-resistant oral penicillins: oxacillin, cloxacillin, dicloxacillin; beta-lactamase-sensitive broad-spectrum oral penicillins: ampicillin, amoxicillin; beta-lactamase-sensitive broad-spectrum parenteral penicillins: piperacillin.
What chemical feature of methicillin confers resistance to hydrolysis by beta-lactamases?
Methicillin has 2 methoxy groups ortho to the carbonyl, which sterically hinders hydrolysis by the enzyme. It is not hydrolzyed by beta-lactamase
Why is methicillin unstable to hydrolysis under acidic conditions?
Electron donation towards the amide carbonyl oxygen by the o-methoxy groups makes the amide carbonyl oxygen more nucleophilic.
What is the antimicrobial spectrum of methicillin?
The antimicrobial spectrum is narrow, and many bacteria are now resistant to it.
Why is MRSA resistant to methicillin?
MRSA is resistant due to a mutation in a penicillin-binding protein (transpeptidase) coded by the mecA gene, which does not react with methicillin.
The PBP that it codes for is called PBP2A
What is the beta-lactamase sensitivity and acid stability of nafcillin?
Nafcillin is not sensitive to beta-lactamases and is slightly more stable than methicillin in acid.
What structural similarities exist among oxacillin, cloxacillin, and dicloxacillin?
They are all isoxazoles.
What is the beta-lactamase sensitivity of oxacillin, cloxacillin, and dicloxacillin?
They are not sensitive to beta-lactamases due to the hindrance from benzene rings.
What is the antimicrobial spectrum of ampicillin?
Ampicillin has a spectrum shifted more toward gram-(-) bacteria due to its ability to pass through porins.
The porins are polar and the primary amino group in side chain is protonated at physiologic pH, have a fixed (+) charged making it a polar molecule
Why is ampicillin stable in acid?
The amino group is protonated in the stomach, decreasing the nucleophilicity of the amide carbonyl oxygen.
What is the main difference in absorption between amoxicillin and ampicillin?
Amoxicillin has better oral absorption than ampicillin due to a carrier needed for transport.
How do beta-lactamase inhibitors like clavulanic acid and sulbactam work?
They acylate the serine hydroxyl group in the active site of beta-lactamase, inactivating the enzyme.
Beta-lactamase inhibitors enhacne the activities of beta-lactamase sensitive beta-lactams.
What structural feature gives acylureidopenicillins like piperacillin a broadened spectrum?
Piperacillin incorporates a urea moiety, enhancing activity against both gram-(+) and gram-(-) bacteria.
Why might piperacillin have enhanced potency?
The added side chain fragment resembles a longer section of the peptidoglycan chain than ampicillin does.
