Antibacterial drugs Flashcards
what color are G+
dark purple
what color are G-
light pink
difference between G+ and G- bacteria
G+ have one bacterial cell membrane
G- have cell membrane-> inner and outer
can drugs penetrate G+ bacteria?
yes
can drugs penetrate G- bacteria?
Not readily
-must go through channels called porins
is the peptigoglycan layer thick or thin in G+
thick
-G- is thin
where are the beta-lactamases in G-?
in the periplasmic layer
-in G+, free
what is the difference between peptidogylcan structure in G+ and G-
G - have meso-diaminopimetic acid
G+ that group is a lysiene
in G- cells, what happens to peptidogylcan?
cross-linking by a bridge between the DAP residue of one strand and the terminal D-Ala of another
what is the cross-linking done by?
transpeptidase
- attacks carbonyl-> forms tetrahedral intermediate (unstable)
- peptidogylcan is linked via an ester bond-> then attacked by amine-> another tetrahedral intermediate-> linked peptidogylcan
beta-lactam MOA
acylate the transpeptidase ser residue in the enzyme active site to form a stable product-> inactivates enzyme, inhibiting peptidoglycan cross-linking-> results in a defective bacterial cell wall-> osmotic cell stress-> cell lysis and cell death.
why is beta-lactam so reactive?
- ) ring strain, carbonyl angle is 90 degrees
- ) folded ring structure N lone pair does not overlap with C=O, more reactive carbonyl because more like ketone than an amide carbonyl
resistance mechanism
mutation of penicillin binding protein
antibiotics are pumped out of cell
production of beta-lactamases
decreased cellular uptake of drug
what is an important characteristic of beta-lactamases activity?
hydrolysis of acylated beta-lactamase intermediate is very fast
-enzyme can hydrolyze many drug molecules quickly
where does the beta-lactam act for those who are allergic?
drug acts as a hapten
-acylates host cell proteins, which then raise antibiotics and results in an allergic reaction
test for penicillin allergy
topical flare and wheal test
how is penicillin degraded?
in acidic conditions and basic conditions
how do you determine if penicillin will be degraded in acidic or basic conditions
electronegativity of R group on penicillin
-Pen G->has carbon-> carbonyl is more reaction
Pen V: has an O-> pulls electron density away from the carbonyl-> less reactive in stomach
what should penicillin solutions be kept away from
heavy metal ions (catalyze penicillin degradation)
serum protein binding: Penicillin
more lipophilic side chains-> more highly protein bound
what does protein binding do to penicillin bioavailablity?
decreases it
-reduces effective concentration of free drug
what is co-administered with penicillin to prolong half life?
probenecid
-competes for tubular secretion with penicillin-> increases its half-life, both are anionic
is Benzylpenicillin (Pen G) beta-lactamase sensitive?
yes
Drug of choice for treating infections
-neisseria, hem. Influenza
- acute allergic reactions
is Methicillin beta-lactamase sensitive?
No
-b/c of steric hinderance of nucleophilic attack by the enzyme on the beta-lactam carbonyl
why doesn’t methicillin administered orally?
unstable in acid stomach-> must be injected
-instability due to electron donation toward the amide carbonyl oxygen by the methoxy groups-> makes amide carbonyl oxygen more reactive
Cephapirin
cephalosporin antibiotic
- six membered sulfur containing ring fused with beta-lactam
- same MOA of penicillin
- beta-lactamase sensitive
how are Cephalosporins made inactive?
if have an acetate in 3-position are metabolically inactivated by hydrolysis of acetate by host esterase-> hydroxymethyl acid that lactonizes
imipenem
carbapenems, carbon analogs of penicillin
- inhitbit beta-lactamase
- used for G+ and G-
why is ring strain greater in carbapenems like impenem
sulfur is present in thiazolidine ring is a methylene group-> increases reactivity b/c methylene is smaller than sulfur
what is imipenem co-administered with?
cilastatin sodium
-imipenem is hydrolyzed by renal dehydropeptiase-1 and this blocks that
how is imipenem and cilastatin sodium administered?
parenterally
-infections of gut, GU tract, bone, skin and endocardium
Aztreonam
synthetic
-inspired by monocyclic beta-lactam natural products called monobactams
what is aztreonam used for?
G- bacteria, especially those by penicillin resistant organisms acquired in hospitals
cross allergenicity has been seen with penicillins and cephalosporins with what antibiotic?
ceftazidime
what is the main difference between aztreonam and penicillins/cephalosporins?
has a sulfamic acid group instead of carboxyl group
Penicillin V
more stable to hydrolysis in stomach than Pen G because electronegativity of the ether oxygen decreases the nucleophilicity of the amide carbonyl
What does protein binding do for penicillin
Protects from degradation
Why aren’t the half life’s of penicillin affected by protein binding?
- Dissociate from protein fast
2. Renal excretion rates are rate limiting
More lipophilic side chains mew what for penicillin
More highly protein bound
Who should avoid taking Pen G
Histories of significant allergies or asthma
Methicillin can treat
Staph aureus
Not MRSA tho
What causes aztreonam to be more reactive with penicillin binding proteins?
Electro negativity of sulfamic acid activates the beta-lactam ring toward hydrolysis and to reaction with penicillin binding proteins
