Main barrier keeping drugs out of cell in gram positive
Gram positives excrete...
B lactamase through the cell wall into the external environment
Outer membrane barrier property in gram negative?
excludes drugs, but some may stil get in through porins in the OUTER cell membrane
In gram negatives, where is the beta lactamase located?
in the periplasmic space
type with thicker PG
Gram negatives have an ____ that contains ____ which may facilitate entry
G- Peptidoglycan contains _______
meso-diaminopimelic acid residue
G+ peptidoglycan contains ____ instead of the ____ that gram negative contains
Crosslinking occurs in G- between the ___ and ____
DAP and D-ala
G+ crosslinking occurs between...
L-Lys and terminal D-ala
S. aureus crosslink composition
5 glycine residues
The OH from ___ attacks the ___ carbon of peptide-d-ala-d-ala
OH from Transpeptidase attacks the amide carbon
Transpeptidase mechanism: ____ is formed as an intermediate which is more reactive
After the ester linkage is broken, a ____ intermediate is formed.
Final products of transpeptidase mechanism
Peptide- D-Ala-Gly-Gly -Peptide
acylates the transpeptidase's serine residue in the enzyme active site.
--> inactivates the enzymes and inhibits cross linking.
reactivity of B lactam system is due to...
highly strained 4-membered ring
NCC bind of the B lactam is compressed to ___ from _____
compressed to 90 from normal 120 angle
Bond angle of a tetrahedral carbon
Stress can be releived in beta lactam strain by conversion of...
carbonyl to the tetrahydral intermediate
The beta lactal carbonyl is more reactive because...
its more like a ketone carbonyl than an amide carbonyl, because of the steric inhibition of overlap of the non-bonded electrons of the nitrogen with the adjacent carbonyl.
Penicillins assume a _____ structure with _____
folded ring structure with an sp3 hybridized nitrogen
There are many ____ which explains the heterogenecity of bacterial responses
penicillin binding proteins
The bacterial transpeptidases do not catalyze rxns with host cell proteins because...
the bacterial substrate contains unnatural D-ala residues that arent found in host cell proteins
Four mechanisms of resistance to beta-lactam
decreased cellular uptake
mutation of the PBPs
Presence of efflux pump
**Induction/elaboration of B-lactamases**
Four steps in B lactamase mechanism
[B lactamase + Penicillin] -->
Tetrahedral intermediate -->
Acylated B lactamase -->
[Regenerated enzyme + hydrolyzed penicillin]
Fast step in beta lactamase mechanism =
Hydrolysis of the acylated B-lactamase intermediate
__% of population has beta-lactam AB's
How are beta lactams allergenic?
Drug acts as hapten - acylates host cell proteins
(generates covalent products that are "foreign")
Why can't the allergic reaction of beta lactam be overcome via structural manipulation of the compound?
the reaction originates from the pharmacore of the drug