Med Chem - Cell Wall Synthesis + Penicillins + Cephalosporins

Question 1

what does fosfomycin inhibit?

Answer 1

PEP transferase

it’s a CELL WALL SYNTHESIS INHIBITOR

Question 2

EXPLAIN how fosfomycin inhibiting PEP transferase is able to inhibit bacterial cell wall synthesis

Answer 2

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

Question 3

How is cycloserine a cell wall synthesis inhibitor

Answer 3

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

Question 4

How is vancomycin a cell wall synthesis inhibitor

Answer 4

it prevents the addition of D-Ala-D-Ala to the tripeptide by binding to it

prevents the formation of the UDP-NAM pentapeptide

Question 5

how does bacitracin work as a cell wall synthesis inhibitor

Answer 5

it blocks the phospholipid carrier from transporting glycopeptide monomers from the cytoplasm to the surface –where the growing cell wall is (UDP-NAM-pentapeptide)

Question 6

explain how beta lactams are able to inhibit cell wall synthesis

Answer 6

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

Question 7

why are cell wall agents considered bactericidal

Answer 7

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

Question 8

to undergo cross linking, the amine on glycine attacks what position?

Answer 8

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

Question 9

true or false

the mechanism in which BOTH beta lactamase and PBP work is through nucleophilic attack by serine OH

Answer 9

TRUE

Question 10

how do beta lactams work to inhibit D-ala transpeptidase

Answer 10

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

Question 11

differentiate between the gram positive and negative cell wall as far as membranes/peptidoglycan layer

Answer 11

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

Question 12

differentiate between the location/access of PBP enzymes between gram positive and negative

Answer 12

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

Question 13

in which are the production of beta lactamases more prevalent — gram (+) or (-)??

where are they located?

Answer 13

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

Question 14

true or false

the early penicillins work against gram (-) bacteria

Answer 14

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

Question 15

TRUE OR FALSE

penicillins are irreversible inhibitors of PBP (D-Ala transpeptidase)

Answer 15

TRUE

covalently acylate the enzyme

Question 16

what were the prototype penicillin molecules

Answer 16

penicillin V (ORAL)
penicillin G (IV)

Question 17

true or false

penicillins are weak acids

Answer 17

TRUE

all have 3-COOH which is ESSENTIAL for its activity

Question 18

explain the pharmacophore of penicillins

Answer 18

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

Question 19

true or false

penicillins are neutral

Answer 19

FALSE

they are weak acids because of COOH at the 3 position

Question 20

what is the MOST CRITICAL structural component of penicillins that is absolutely essential for their activity

Answer 20

the beta lactam ring

HOWEVER, the beta lactam alone is not enough for activity - must be fused with 5-membered thiazolidine ring

Question 21

what is structure of thiazolidine

Answer 21

look at name - “thi” = sulfur”
“az” = nitrogen

5 membered ring fused with sulfur and nitrogen (S at 1 and N at 4)

Question 22

true or false

penicillins do not structurally mimic anything

Answer 22

FALSE

they do
structurally mimic D-Ala-D-ala

Question 23

name the only 2 true orally stable penicillins and WHY they are

Answer 23

ampicillin and amoxicillin
have amino group on alpha carbon

Question 24

what were the prototype penicillins

Answer 24

Penicillin G (IV)
Penicillin V (PO)

Question 25

name 5 penicillins that are "antistaphylococcal" and what does this mean

Answer 25

they are resistant to penicillinase methicillin oxacillin cloxacillin nafcillin dicloxacillin bulky, aromatic, lipophilic group

Question 26

name 2 penicillins in the "carboxy-penicillin" class and what are their features

Answer 26

carbenicillin, ticarcillin have alpha carboxy group, which gives additional gram (-) spectrum of activity

Question 27

"3rd gen penicillins" examples and features

Answer 27

piperacillin and mezlocillin have acyl ureido group which broadens their spectrum of activity to gram (+) + some gram (-)

Question 28

true or false all penicillins are unstable under acidic conditions

Answer 28

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

Question 29

true or false while amino substitution on the alpha carbon makes penicillins orally stable, they are detrimental to the antibacterial property of the drug

Answer 29

FALSE does not decrease antibacterial activity the b lactam ring is most critical for the acylation of PBP

Question 30

2 key structural components to look for when seeing if a penicillin or cephalosporin is used orally

Answer 30

amine on alpha carbon COOH protected by R3 group (cephalosporin -- only if no alpha amine)

Question 31

differentiate between the pharmacophore of penicillin vs cephalosporins

Answer 31

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

Question 32

cephalosporins have a chemical structure related to penicillins but with a modified ______ system, allowing for __________

Answer 32

modified bicyclic system, allowing for further SUBSTITUTION (thus a highly rich area for chemical modifications)

Question 33

how many modification positions are there on penicillins vs cephalosporins

Answer 33

penicillins only have 1 and cephalosporins have 3

Question 34

to be orally fit, penicillins and cephalosporins must either have an alpha amine or protection of COOH (cephalosporins) name 2 exceptions

Answer 34

cefixime and ceftibuten dont have alpha amine AND dont have COOH protection from R3

Question 35

differentiate between the structures of early gen (1st-2nd) oral cephalosporins vs later gen oral cephalosporins

Answer 35

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!!

Question 36

which cephalosporin is actually 2nd gen oral but its structure is like the later gens

Answer 36

cefuroxime axetil (easy to remember! has oxime in the name)

Question 37

explain the significance of later gen oral cephalosporins having a bulky R group

Answer 37

they are prodrugs!!! need to be hydrolyzed to expose COOH and produce an active molecule

Question 38

true or false 3rd and later generations of cephalosporins have greater gram (-) activity than the 1st 2

Answer 38

TRU have different structure - oxime

Question 39

bioisostere of oxime that replaced oxime in the structure of ceftibuten

Answer 39

C=C-C

Question 40

differentiate between the structures of early gen (1-2) parenteral cephalosporins vs later gen PARENTERAL cephalosporins

Answer 40

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

Question 41

how can you differentiate between an oral vs parenteral cephalosporin by looking at the structure

Answer 41

to be oral - need to look for alpha amine on R1 component or a bulky R3 to protect COOH

Question 42

differentiate between the number of R substitutions between oral and parenteral cephalosporins

Answer 42

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

Question 43

Which cephalosporins (in general - not specific) have the bleeding issue

Answer 43

some parenteral cephalosporins bc of MTT on R2 (methylthiotetrazole)

Question 44

which cephalosporin has an issue of causing kidney damage and why

Answer 44

cephalothin bc of thiophene portion of R1 (basically thiazole - 5 membered heterocycle with S)

Question 45

true or false parenteral cephalosporins having a very bulky R2 group is a disadvantage because it's very acid labile

Answer 45

FALSE while it is very acid labile, it doesn't matter because it's bypassing the GI anyway

Question 46

what structural component gives later generation penicillins (3rd and on) enhanced activity against gram (-) organisms like pseudomonas?

Answer 46

OXIME

Question 47

ceftazidime + ________ = ______

Answer 47

avibactam = AVYCAZ

Question 48

what is avibactam

Answer 48

a non beta lactam beta lactamase inhibitor that can be combined with cefazidime (3rd gen parenteral ceph) to form brand name AVYCAZ

Question 49

what can avycaz be used for and why

Answer 49

(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

Question 50

name of the "1st 4th generation" cephalosporin that was founded to overcome resistance issues with 3rd gen name a structural characteristic of it

Answer 50

cefpirome has a cyclopentane fused with a pyridinium ion in R2 side chain

Question 51

cefpirome is ____ like

Answer 51

cefotaxime

Question 52

avycaz = ____ + ____

Answer 52

ceftazidime (3rd gen parenteral) + avibactam

Question 53

true or false avibactam is a non beta lactam beta lactamase inhibitor

Answer 53

TRUE

Question 54

zerbaxa

Answer 54

ceftolozane + tazobactam

Question 55

4 indications of zerbaxa

Answer 55

intra abdominal infections complicated UTIs hospital acquired bacterial pneumonia ventilator associated bacterial pneumonia

Question 56

true or false zerbaxa is not active against pseudomonas

Answer 56

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)

Question 57

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

Answer 57

ceftaroline fosamil NOT active against psuedomonas or ESBL-producing strains (extended spectrum beta lactamases)

Question 58

true or false ceftaroline is a good substrate for CYP P 450 enzymes, making it have a lot of drug drug interactions

Answer 58

FALSE poor substrate no DDI related to P450

Question 59

true or false ceftaroline is a prodrug

Answer 59

TRUE it's a phosphoramide prodrug that needs to be hydrolyzed in vivo by plasma phosphatase to expose the FREE AMINO (NH2)

Question 60

name another 5th gen cephalosporin aside from ceftaroline fosamil

Answer 60

ceftobiprole medocaril

Question 61

true or false cephalsoporins are acidic

Answer 61

true

Question 62

early generation oral cephalosporins have what kind of R1 side chain

Answer 62

BENZENE (sub or unsub) with an alpha amino attached