Med Chem - Cell Wall Synthesis + Penicillins + Cephalosporins Flashcards
what does fosfomycin inhibit?
PEP transferase
it’s a CELL WALL SYNTHESIS INHIBITOR
EXPLAIN how fosfomycin inhibiting PEP transferase is able to inhibit bacterial cell wall synthesis
PEP transferase is responsible for converting UDP-NAG + PEP into
UDP-NAG-enolpyruvate, which then turns into UDP-NAM
UDP-NAM is then attached to D-Ala-Glu-Lys which is ESSENTIAL for cell well synthesis. This turns into a pentapeptide (with D-ala-D-ala being terminal)
thus, when PEP transferase is inhibited by fosfomycin, it prevents the initial step of generating UDP-NAM
How is cycloserine a cell wall synthesis inhibitor
it inhibits alanine racemerase, the enzyme responsible for both converting L-Ala to D-Ala and D-Ala into D-ala-D-ala which binds the tripeptide on UDP-NAM to form a PENTAPEPTIDE
How is vancomycin a cell wall synthesis inhibitor
it prevents the addition of D-Ala-D-Ala to the tripeptide by binding to it
prevents the formation of the UDP-NAM pentapeptide
how does bacitracin work as a cell wall synthesis inhibitor
it blocks the phospholipid carrier from transporting glycopeptide monomers from the cytoplasm to the surface –where the growing cell wall is (UDP-NAM-pentapeptide)
explain how beta lactams are able to inhibit cell wall synthesis
they prevent the last and very important step of cell wall synthesis – CROSS LINKING for a strong peptidoglycan structure with structural integrity
normally, without a beta lactam, the NH2 on GLYCINE would attack the 2nd to terminal D-Ala to FORM A VERY STRONG COVALENT BOND TO THE CARBONYL on the adjacent structure and kick off the terminal D-Ala. this is done through the enzyme D-ALA TRANSPEPTIDASE (PBP)
HOWEVER, BETA LACTAMS INHIBIT THIS ENZYME AND THUS PREVENT THE CROSS LINKING FOR STRUCTURAL INTEGRITY
why are cell wall agents considered bactericidal
because without a functional cell wall, the bacteria will burst due to the osmotic pressure causing water to rush into the bacteria without a cell wall as a barrier
to undergo cross linking, the amine on glycine attacks what position?
between the 4-5 position of the tripeptide (between both D-ala’s)
bond is hydrolyzed and the terminal D-Ala is kicked off and a covalent bond to a carbonyl is formed
NH-C=O
true or false
the mechanism in which BOTH beta lactamase and PBP work is through nucleophilic attack by serine OH
TRUE
how do beta lactams work to inhibit D-ala transpeptidase
mimics D-Ala-D-ala dipeptide
thus, the Ser-OH on PBP will attack the beta lactam, thinking it is D-Ala-D-Ala!!
this will form a COVALENTLY ACYLATED ENZYME that can no longer be active in forming strong crosslinks for the cell wall
differentiate between the gram positive and negative cell wall as far as membranes/peptidoglycan layer
gram positve - only has 1 membrane and it’s BELOW the THICK PEPTIDOGLYCAN CELL WALL. thus, the cell wall is relatively readily exposed
gram negative - has AN OUTER AND INNER MEMBRANE with a THIN peptidoglycan layer in between. much harder to get to
differentiate between the location/access of PBP enzymes between gram positive and negative
gram positive - located just under the thick peptidoglycan layer at the surface of the underlying membrane. relatively easy to access
gram negative - located also just under the THIN peptidoglycan layer at the surface of the underlying membrane. HOWEVER, there is a whole upper membrane the drug has to get through before the PBP enzymes can be accessed for inhibition
in which are the production of beta lactamases more prevalent — gram (+) or (-)??
where are they located?
gram (-)
located in a similar position as the PBP’s – just at the upper surface of the lower membrane, directly below the thin peptidoglycan cell wall
true or false
the early penicillins work against gram (-) bacteria
FALSE
they do NOT. the gram (-) bacteria produce penicillinases (B lactamases)
HOWEVER the later gen penicillins are more active against gram (-)
ie - carboxy penicillins, those with acyl ureido, and the bulky aromatic lipophilic group
BC RELATIVELY RESISTANT TO BETA LACTAMASES
TRUE OR FALSE
penicillins are irreversible inhibitors of PBP (D-Ala transpeptidase)
TRUE
covalently acylate the enzyme
what were the prototype penicillin molecules
penicillin V (ORAL)
penicillin G (IV)
true or false
penicillins are weak acids
TRUE
all have 3-COOH which is ESSENTIAL for its activity
explain the pharmacophore of penicillins
have beta lactam ring (4 membered) fused with a thiazolidone ring (5 membered)
ALL have carboxyamino attached to beta lactam ring, with the R substituent being the ONLY PLACE for structural changes
there are 2 methyl groups attached to position 2 on thiazolidine
ALL have COOH at the 3 position which is essential
true or false
penicillins are neutral
FALSE
they are weak acids because of COOH at the 3 position
what is the MOST CRITICAL structural component of penicillins that is absolutely essential for their activity
the beta lactam ring
HOWEVER, the beta lactam alone is not enough for activity - must be fused with 5-membered thiazolidine ring
what is structure of thiazolidine
look at name - “thi” = sulfur”
“az” = nitrogen
5 membered ring fused with sulfur and nitrogen (S at 1 and N at 4)
true or false
penicillins do not structurally mimic anything
FALSE
they do
structurally mimic D-Ala-D-ala
name the only 2 true orally stable penicillins and WHY they are
ampicillin and amoxicillin
have amino group on alpha carbon
what were the prototype penicillins
Penicillin G (IV)
Penicillin V (PO)
name 5 penicillins that are “antistaphylococcal” and what does this mean
they are resistant to penicillinase
methicillin
oxacillin
cloxacillin
nafcillin
dicloxacillin
bulky, aromatic, lipophilic group
name 2 penicillins in the “carboxy-penicillin” class and what are their features
carbenicillin, ticarcillin
have alpha carboxy group, which gives additional gram (-) spectrum of activity
“3rd gen penicillins”
examples and features
piperacillin and mezlocillin
have acyl ureido group which broadens their spectrum of activity to gram (+) + some gram (-)
true or false
all penicillins are unstable under acidic conditions
FALSE - most but not all
ampicillin and amoxicillin are stable under oral conditions (acidic)
penicillin V can still be given orally, but have to administer more dose because a lot will get destroyed in the GI tract before its absorbed. this is allowed because of the high therapeutic index
true or false
while amino substitution on the alpha carbon makes penicillins orally stable, they are detrimental to the antibacterial property of the drug
FALSE
does not decrease antibacterial activity
the b lactam ring is most critical for the acylation of PBP
2 key structural components to look for when seeing if a penicillin or cephalosporin is used orally
amine on alpha carbon
COOH protected by R3 group (cephalosporin – only if no alpha amine)
differentiate between the pharmacophore of penicillin vs cephalosporins
penicillins have thiazolidine (5 membered) fused with beta lactam ring.
cephalosporins have dihydrothiazine (6 membered) fused with beta lactam ring. (this change allows for R2 substitution at the 3 position on dihydrothiazine)
in penicillins, the COOH group at position 3 is UNPROTECTED
in cephalosporins, the COOH group is PROTECTED (sometimes - usually later oral gens with no alpha amine) with an R3 group attached to the terminal O, protecting it for ORAL USE
cephalosporins have a chemical structure related to penicillins but with a modified ______ system, allowing for __________
modified bicyclic system, allowing for further SUBSTITUTION
(thus a highly rich area for chemical modifications)
how many modification positions are there on penicillins vs cephalosporins
penicillins only have 1 and cephalosporins have 3
to be orally fit, penicillins and cephalosporins must either have an alpha amine or protection of COOH (cephalosporins)
name 2 exceptions
cefixime and ceftibuten dont have alpha amine AND dont have COOH protection from R3
differentiate between the structures of early gen (1st-2nd) oral cephalosporins vs later gen oral cephalosporins
early gen: all have benzene (substituted or unsubstituted) R1 group with an alpha amine attached to the alpha carbon (orally fit!!). also, R3 is always H and R2 is simple (CH3, Cl, etc)
later gen: instead of benzene, it’s a 5-membered heterocycle like furan, thiazole, or thiazole substituted with amine. also, instead of alpha amine attached to alpha carbon, there is an OXIME group attached to the ring (C=NO). THEREFORE, since there is no alpha amine, must have COOH protection with a bulky R3 group (most cases - exceptions are cefixime and ceftibuten) to be orally fit!!
which cephalosporin is actually 2nd gen oral but its structure is like the later gens
cefuroxime axetil
(easy to remember! has oxime in the name)
explain the significance of later gen oral cephalosporins having a bulky R group
they are prodrugs!!!
need to be hydrolyzed to expose COOH and produce an active molecule
true or false
3rd and later generations of cephalosporins have greater gram (-) activity than the 1st 2
TRU
have different structure - oxime
bioisostere of oxime that replaced oxime in the structure of ceftibuten
C=C-C
differentiate between the structures of early gen (1-2) parenteral cephalosporins vs later gen PARENTERAL cephalosporins
early gen - has UNSUBSTITUTED aromatic heterocyclic or benzene ring as R1. R2 very bulky
later gen - HAVE AMINO-THIAZOLE + OXIME COMBO AS R1. R2 also very bulky
how can you differentiate between an oral vs parenteral cephalosporin by looking at the structure
to be oral - need to look for alpha amine on R1 component or a bulky R3 to protect COOH
differentiate between the number of R substitutions between oral and parenteral cephalosporins
oral have 3
parenteral only hav 2 – dont need R3 to protect the COOH because it’s being injected and bypassing the hostile GI conditions
Which cephalosporins (in general - not specific) have the bleeding issue
some parenteral cephalosporins
bc of MTT on R2 (methylthiotetrazole)
which cephalosporin has an issue of causing kidney damage and why
cephalothin bc of thiophene portion of R1
(basically thiazole - 5 membered heterocycle with S)
true or false
parenteral cephalosporins having a very bulky R2 group is a disadvantage because it’s very acid labile
FALSE
while it is very acid labile, it doesn’t matter because it’s bypassing the GI anyway
what structural component gives later generation penicillins (3rd and on) enhanced activity against gram (-) organisms like pseudomonas?
OXIME
ceftazidime + ________ = ______
avibactam = AVYCAZ
what is avibactam
a non beta lactam beta lactamase inhibitor that can be combined with cefazidime (3rd gen parenteral ceph) to form brand name AVYCAZ
what can avycaz be used for and why
(ceftazidime + avibactam)
avycaz in combination with metronidazole can treat complicated intra-abdominal infections caused by gram (-) organisms like pseudomonas
this is bc the extra COOH connected to oxime on ceftazidime gives enhanced activity and potency against pseudomonas, and also the R2 group on ceftazidine includes pyridinium ion, which is a GOOD LEAVING GROUP
this pyridinium ion is the driving force for the acylation of PBP enzyme. pyridinium leaves as pyridine
name of the “1st 4th generation” cephalosporin that was founded to overcome resistance issues with 3rd gen
name a structural characteristic of it
cefpirome
has a cyclopentane fused with a pyridinium ion in R2 side chain
cefpirome is ____ like
cefotaxime
avycaz = ____ + ____
ceftazidime (3rd gen parenteral) + avibactam
true or false
avibactam is a non beta lactam beta lactamase inhibitor
TRUE
zerbaxa
ceftolozane + tazobactam
4 indications of zerbaxa
intra abdominal infections
complicated UTIs
hospital acquired bacterial pneumonia
ventilator associated bacterial pneumonia
true or false
zerbaxa is not active against pseudomonas
FALSE
it is
used to treat nosocomial infections like ventilator associated and hospital acquired bacterial pneumonia
(major causes of morbidity and mortality is hospital pts)
5th gen cephalosporine that has a extremely wide range of activity against MRSA, including vanco and dapto resistant strains and enterococcus
name 2 things it is NOT active against
ceftaroline fosamil
NOT active against psuedomonas or ESBL-producing strains (extended spectrum beta lactamases)
true or false
ceftaroline is a good substrate for CYP P 450 enzymes, making it have a lot of drug drug interactions
FALSE
poor substrate
no DDI related to P450
true or false
ceftaroline is a prodrug
TRUE
it’s a phosphoramide prodrug that needs to be hydrolyzed in vivo by plasma phosphatase to expose the FREE AMINO (NH2)
name another 5th gen cephalosporin aside from ceftaroline fosamil
ceftobiprole medocaril
true or false
cephalsoporins are acidic
true
early generation oral cephalosporins have what kind of R1 side chain
BENZENE (sub or unsub) with an alpha amino attached
