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D&D Infectious Disease Midterm > Med Chem - Cell Wall Synthesis + Penicillins + Cephalosporins > Flashcards

Med Chem - Cell Wall Synthesis + Penicillins + Cephalosporins Flashcards

1
Q

what does fosfomycin inhibit?

A

PEP transferase

it’s a CELL WALL SYNTHESIS INHIBITOR

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2
Q

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

A

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

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3
Q

How is cycloserine a cell wall synthesis inhibitor

A

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

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4
Q

How is vancomycin a cell wall synthesis inhibitor

A

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

prevents the formation of the UDP-NAM pentapeptide

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5
Q

how does bacitracin work as a cell wall synthesis inhibitor

A

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

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6
Q

explain how beta lactams are able to inhibit cell wall synthesis

A

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

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7
Q

why are cell wall agents considered bactericidal

A

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

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8
Q

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

A

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

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9
Q

true or false

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

A

TRUE

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10
Q

how do beta lactams work to inhibit D-ala transpeptidase

A

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

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11
Q

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

A

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

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12
Q

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

A

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

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13
Q

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

where are they located?

A

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

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14
Q

true or false

the early penicillins work against gram (-) bacteria

A

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

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15
Q

TRUE OR FALSE

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

A

TRUE

covalently acylate the enzyme

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16
Q

what were the prototype penicillin molecules

A

penicillin V (ORAL)
penicillin G (IV)

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17
Q

true or false

penicillins are weak acids

A

TRUE

all have 3-COOH which is ESSENTIAL for its activity

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18
Q

explain the pharmacophore of penicillins

A

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

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19
Q

true or false

penicillins are neutral

A

FALSE

they are weak acids because of COOH at the 3 position

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20
Q

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

A

the beta lactam ring

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

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21
Q

what is structure of thiazolidine

A

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

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

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22
Q

true or false

penicillins do not structurally mimic anything

A

FALSE

they do
structurally mimic D-Ala-D-ala

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23
Q

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

A

ampicillin and amoxicillin
have amino group on alpha carbon

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24
Q

what were the prototype penicillins

A

Penicillin G (IV)
Penicillin V (PO)

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25
Q

name 5 penicillins that are “antistaphylococcal” and what does this mean

A

they are resistant to penicillinase

methicillin
oxacillin
cloxacillin
nafcillin
dicloxacillin

bulky, aromatic, lipophilic group

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26
Q

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

A

carbenicillin, ticarcillin

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

27
Q

“3rd gen penicillins”

examples and features

A

piperacillin and mezlocillin

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

28
Q

true or false

all penicillins are unstable under acidic conditions

A

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

29
Q

true or false

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

A

FALSE

does not decrease antibacterial activity

the b lactam ring is most critical for the acylation of PBP

30
Q

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

A

amine on alpha carbon

COOH protected by R3 group (cephalosporin – only if no alpha amine)

31
Q

differentiate between the pharmacophore of penicillin vs cephalosporins

A

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

32
Q

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

A

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

33
Q

how many modification positions are there on penicillins vs cephalosporins

A

penicillins only have 1 and cephalosporins have 3

34
Q

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

name 2 exceptions

A

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

35
Q

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

A

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!!

36
Q

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

A

cefuroxime axetil

(easy to remember! has oxime in the name)

37
Q

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

A

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

38
Q

true or false

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

A

TRU

have different structure - oxime

39
Q

bioisostere of oxime that replaced oxime in the structure of ceftibuten

A

C=C-C

40
Q

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

A

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

41
Q

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

A

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

42
Q

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

A

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

43
Q

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

A

some parenteral cephalosporins

bc of MTT on R2 (methylthiotetrazole)

44
Q

which cephalosporin has an issue of causing kidney damage and why

A

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

45
Q

true or false

parenteral cephalosporins having a very bulky R2 group is a disadvantage because it’s very acid labile

A

FALSE

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

46
Q

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

A

OXIME

47
Q

ceftazidime + ________ = ______

A

avibactam = AVYCAZ

48
Q

what is avibactam

A

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

49
Q

what can avycaz be used for and why

A

(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

50
Q

name of the “1st 4th generation” cephalosporin that was founded to overcome resistance issues with 3rd gen

name a structural characteristic of it

A

cefpirome

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

51
Q

cefpirome is ____ like

A

cefotaxime

52
Q

avycaz = ____ + ____

A

ceftazidime (3rd gen parenteral) + avibactam

53
Q

true or false

avibactam is a non beta lactam beta lactamase inhibitor

A

TRUE

54
Q

zerbaxa

A

ceftolozane + tazobactam

55
Q

4 indications of zerbaxa

A

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

56
Q

true or false

zerbaxa is not active against pseudomonas

A

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)

57
Q

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

A

ceftaroline fosamil

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

58
Q

true or false

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

A

FALSE

poor substrate

no DDI related to P450

59
Q

true or false

ceftaroline is a prodrug

A

TRUE

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

60
Q

name another 5th gen cephalosporin aside from ceftaroline fosamil

A

ceftobiprole medocaril

61
Q

true or false

cephalsoporins are acidic

A

true

62
Q

early generation oral cephalosporins have what kind of R1 side chain

A

BENZENE (sub or unsub) with an alpha amino attached

63
Q
A

D&D Infectious Disease Midterm (26 decks)

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