Antibacterials - Penicillins Flashcards
Gram positive bacteria stain
dark purple
Gram negative bacteria stain
light pink
Gram+ and Gram- bacteria differ in the structure of their _____ (general)
cell walls
What is the difference between Gram+ and Gram- bacteria in terms of drug penetration?
In gram+, drugs can penetrate the outer layers of the cell wall effectively and the bacterial membrane is the main barrier keeping drugs out of the cell
In gram-, the outer membrane excludes drugs, but some drugs can still get in through the porins in the outer membrane
What is the difference between Gram+ and Gram- bacteria in terms of beta lactamases?
In gram+, b-lactamases are excreted through the cell wall to the external environment. Therefore, they have to produce them in greater quantities.
In gram-, b-lactamases are confied to the periplasmic space
What is the difference between the peptidoglycan layer in gram+ vs gram- bacteria?
In gram+ bacteria, the peptidoglycan layer is much thicker than in gram-
What is the difference in membranes in gram+ vs gram- bacteria?
Gram+ have one membrane while gram- have two membranes (and inner and outer). Gram- bacteria therefore have a more complex cell wall that is more lipoidal.
What kind of residues are seen in the peptidoglycan layers of gram+ and gram- bacteria?
Gram- peptidoglycan layer contains a meso-diaminopimelic acid reside (DAP)
Gram+ peptidoglycan have an L-lysine residuce (the COOH of DAP is replaced by an H)
What is the difference in cross-linking b/t the gram+ and gram- cell peptidoglycan layer?
Gram- peptidoglycan is cross-linked by a bridge between the DAP residue of one strand and the terminal D-Ala of another
Gram+, the bridge exists b/t L-lys and the terminal D-ala of the second molecule
Cross link varies b/t species, but is typically ~5 amino acids
What cross-linked the peptidoglycan strands?
transpeptidase
What do B-lactam antibiotics do?
How?
Inhibit the transpeptidases that “glue” the peptidoglycan strands together
B-lactam antibiotics acylate the transpeptidase Ser residue in the enzyme active site to form a stable product. This inactivates the enzyme, inhibiting peptidoglycan cross-linking, which results in defective bacterial wall synthesis
The reactivity of the B-lactam system is due to …
- Ring strain (highly strained 4 member ring in which the bond angle is compressed to 90deg from the normal 120deg)
- Steric inhibition (stersoelectronics are not right to stabilize the carbonyl)
What explains the heterogeneisity of response to different penicillins?
That there are many penicillin-binding proteins which differ from species to species
The bacterial transpeptidases do not catalyze the reactions with host cell proteins because …
the bacterial substrate contains unnatural D-Ala amino acid residues that are not found in the host cell proteins
Resistance to B-Lactam antibiotics may result from …
- Decreased cellular uptake of the drug
- Mutation of the penicillin-binding proteins to decrease their affinity for penicillins
- Presence of an efflux pump that pumps antibiotics out of the cell
The allergenicity of B-Lactam antibiotics results from the drug acting as …
a hapten
It acylates the host cell proteins, which then raise antibodies and result in an allergic reaction
Under acidic conditions, the main degradation products of Pen G are …
- Benzylpenicillenic Acid
- Benzylpenillic Acid
- Benzylpenicilloic Acid
Five important points regarding degradation/hydrolysis of penicillins
- Hydrolysis products have no antibiotic activity
- Hydrolysis of the B-lactam is irreversible
- Electronegative substituents on the side chain carbonyl reduce the nucleophilicity of the side chain amide carbonyl oxygen atom. THIS STABILIZES THE PENICILLIN AGAINST HYDROLYSIS UNDER ACID CONDITIONS AND DECREASES ITS BIOAVAILABILITY
- Solutions of penicillins for parenteral use should be used promptly
- Heavy metal ions catalyze penicillin degradation reactions and should be kept away from penicillin solutions
Serum protein binding and penicillins
- Those with more lipophilic side chains are more highly protein bound
- Protein binding reduces bioavailability by reducing the effective concentration of the free drug
- Protein binding in general protects drugs from degradation
- Half-lives of penicillins are generally no affected by protein binding since their dissociation rates from the protein are fast and the renal excretion rates are rate-limiting
Excretion WRT penicillins
- Rapidly excreted by the renal or biliary routes. In renal routes, 10% glomerular filtrate, 90% tubular secretion.
- Half lives of penicillins excreted by the kidneys are prolonged in cases of kidney disease or failure.
- Penicillins are anionic. When given in combination with probenecid, half life is increased.
Antimicrobial spectrum of Benzylpenicillin (Pen G)
Gram+ cocci plus Neisseria gonorrhoeae and Haemophilus influenzae
Pen G is the drug of choice for treatment of more infections than any other antibiotic
Benzylpenicillin (Pen G)
- B-lactamase sensitive?
- Administration
- Toxicity
- Precaution
Yes, b-lactamase sensitive
Administered orally in large doses, but most effective route is parenteral
Toxicity: acute allergic reactions
Use with caution in individuals with histories of significant allergies and/or asthma
Methicillin
- B-lactamse sensitive?
- Administration
No, it is sterically hindered
Must be administered by injection b/c it is unstable to acid in the stomach
Methicillin antimicrobial spectrum
Used primarily for b-lactamase producing staph aureus
Why is MRSA resistant to methicillin?
Because of a mutation in the penicillin-binding protein (transpeptidase). The gene coding for this protein is called methicillin resistance gene (mecA), and the penicillin binding protein that it codes for is called PBP2’
What is unique about the structure of cephapirin?
It has a six membered sulfur-containing ring fused to the B-lactam instead of a five-membered ring
Is cephapirin b-lactamase sensitive?
yes
Cephalosporins that have an acetate in the 3-position are metabolically inactivated by …
hydrolysis of the acetate by host esterases
this produces a hydroxymethyl acid that lactonizes
Imipenem
- what kind of drug is this? how are these related to penicillins
- what is unique about the structure? what does this do for reactivity?
This is a carbapenem. They are carbon analogs of penicillins.
The sulfur that is present in the thizaolidine ring of the penicillins is replaced by a methylene group. This increases reactivity b/c a methylene is smaller than a sulfur, so the ring strain is greater in the carbapenems.
Besides reacting with penicillin-binding proteins, imipenem …
reacts with and inhibits b-lactamases
Imipenem is hydrolyzed by …
But this can be overcome by …
hydrolyzes by renal dehydropeptidase-1
overcome by co-administration of the dehydropeptidase-1 inhibitor cilastatin
The combination of imipenem and cilastatin has …
This combination is used to treat …
a broader spectrum of antibiotic activity than any other antibiotic presently available in the US
serious infections in the gut, GU tract, bone, skin, and endocardium
Aztreonam is totally …
synthetic
the design was inspired by monocyclic B-lactam natural products called monobactams
What is different about the aztreonam structure as compared with penicillins and cephalosporins?
What does this do for the drug?
The sulfuric acid group takes the place of the C-2 carboxyl group in the penicillins and cephalosporins
The EN of the sulfuric acid activates the B-lactam ring toward hydrolysis and to reaction with penicillin-binding proteins
What is the antibiotic spectrum of aztreonam?
Completely gram- bacteria
Used mainly in the treatment of severe infections with Gram- bacteria
