2: B-lactams Flashcards
G(+) vs. G(-): color on gram stain
G(+): dark purple (crystal violet)
G(-): light pink (safranin)
G(+) vs. G(-): can drugs penetrate the outer layer?
G(+): drugs penetrate outer layer
G(-): drugs can’t penetrate outer layer, but some use porins
G(+) vs. G(-): where are B-lactamases located?
G(+): excrete B-lactamases through cell wall (need more)
G(-): B-lactamases confined to periplasmic space
G(+) vs. G(-): thickness of PG layer?
G(+): thick PG
G(-): thin PG
G(+) vs. G(-): number of membranes?
G(+): one membrane
G(-): two membranes (more lipoidal)
G(+) vs. G(-): L-Lys or DAP in PG?
G(+): L-Lys
G(-): DAP
B-lactam MOA
penicillin resembles D-Ala-D-Ala -> acylates Ser of PBP to form a stable product, inactivating PBP
what gives B-lactam ring its reactivity? 2 reasons
- carbonyl: tetrahedral intermediate 90* compressed angle -> 109* angle
- B-lactam carbonyl is more like a ketone carbonyl (N lone pair doesn’t overlap with C=O) -> more reactive
why don’t bacterial PBPs react with host protein?
bacteria have D-Ala; human proteins do not
4 mechanisms of resistance to B-lactmas
- decreased cell uptake
- mutant PBPs
- efflux pump
* *4. bacterial B-lactamases (hydrolyze B-lactam ring)
what percent of people are allergic to B-lactams?
6-8% of US
cause of B-lactam allergenicity
due to drug acting as hapten and acylating host proteins
range of sx from B-lactam allergy
rash (urticaria) to anaphylaxis
why can’t B-lactams be structurally altered to reduce allergenicity?
b/c allergenicity originates in pharmacophore
how can you test for B-lactam allergy?
topical wheal and flare test
is penicillin degradation in acid reversible or not? what can catalyze degradation?
irreversible
-catalyzed by heavy metal ions
3 major degradation products of penicillin and mechanism of degradation
- benzylpenicillenic acid (eliminate a sulfhydryl from 2nd intermediate)
- Benzylpenillic acid (complex hydrolysis w/ ankemeric assistance)
- Benzylpenicilloic acid (basic solution (-OH))
how can penicillins be stabilized against degradation?
make R group more electronegative -> nucleophilicity of carbonyl is reduced
effect of serum protein binding on penicillins
- reduces bioavailability b/c less [free drug]
- protects from degradation b/c degradation occurs on drugs in solution
- does not change half life b/c fast dissociation rates/ renal excretion rate = limiting factor
how does lipophilicity of R group change serum protein binding?
more lipophilic R = more highly protein bound
excretion of penicillin
rapid:
- biliary
- renal: 10% glomerular filtration, 90% tubular secretion via anionic mechanism
what happens to half life of penicillin if administered to patient with kidney disease?
increase half life
how can one target the anionic mechanism of penicillin excretion to increase its half life?
administer penicillin with probenecid
Benzylpenicillin (Pen G): R group
-benzyl R group
Benzylpenicillin (Pen G): B-lactamase sensitive?
yes
Benzylpenicillin (Pen G): activity
G(+) cocci + N. gonorrhea, H. influenzae
drug of choice for treatment of more stuff than any other antibiotic
Benzylpenicillin (Pen G): admin
p.o. - large dose
parenteral = most effective
Benzylpenicillin (Pen G): toxicity/contraindications
- acute allergic reaction
- don’t give with significant history of asthma/allergies
Methichillin: R group
ortho methoxy groups
Methichillin: B-lactamase sensitive?
no - steric hindrance of methoxyls prevents nucleophilic attack on C=O
Methichillin: admin
injection only (unstable in acid, so no oral)
Methichillin: activity
narrow - mostly for B-lactamase producing S. aureus
Methichillin: toxicity/contraindications
-inducer of B-lactamase, so only use when required
Methichillin: resistance mechanism
PBP2 (mutation in gene mecA)
Cephapirin: structure
cephalosporin w/ 6-member ring w/ S
-acetate at position 3
Imipenem: structure
carbapenem
-S replaced by methylene (greater ring strain)
Imipenem: B-lactamase sensitive? sensitive to anything else?
no - inhibits B lactamases
but, hydrolyzed by renal dehydropeptidase-1 (can be overcome when given w/ cilastatin)
Imipenem: activity
G(+) and G(-)
-serious infections of gut, GU tract, bone, skin, endocardium
“magic bullet” - combo w/ cilastatin has broader activity than any other US antibiotic
Imipenem: admin
parenteral
Imipenem: toxicity/contraindications
good B-lactamase inducer, so only use when required
aztreonam: structure
- synthetic monobactam
- sulfamic acid in place of C=O
aztreonam: activity
almost completely G(-) - especially those by penicillin resistant dudes acquired in hospitals
aztreonam: toxicity/contraindications
-cross allergenicity only reported with ceftazidime (same R group)
aztreonam: what makes the B-lactam ring more reactive?
electronegativity of sulfamic acid
