Antibiotics 1 - Cell wall and Beta Lactams Flashcards Preview

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Flashcards in Antibiotics 1 - Cell wall and Beta Lactams Deck (70):
1

Main barrier keeping drugs out of cell in gram positive

Bacterial membrane

2

Gram positives excrete...

B lactamase through the cell wall into the external environment

3

Outer membrane barrier property in gram negative?

excludes drugs, but some may stil get in through porins in the OUTER cell membrane

4

In gram negatives, where is the beta lactamase located?

in the periplasmic space

5

type with thicker PG

gram positive

6

Gram negatives have an ____ that contains ____ which may facilitate entry

outer membrane

porins

7

G- Peptidoglycan contains _______

meso-diaminopimelic acid residue

(DAP)

8

G+ peptidoglycan contains ____ instead of the ____ that gram negative contains

L-Lysine

DAP

9

Crosslinking occurs in G- between the ___ and ____

DAP and D-ala

10

G+ crosslinking occurs between...

L-Lys and terminal D-ala

11

S. aureus crosslink composition

5 glycine residues

12

Transpeptidase mechanism:

The OH from ___ attacks the ___ carbon of peptide-d-ala-d-ala

OH from Transpeptidase attacks the amide carbon

13

Transpeptidase mechanism: ____ is formed as an intermediate which is more reactive

Ester linkage

14

After the ester linkage is broken, a ____ intermediate is formed. 

tetrahedral

15

Final products of transpeptidase mechanism

Peptide- D-Ala-Gly-Gly -Peptide

+

Transpeptidase

16

B-lactam MOA

acylates the transpeptidase's serine residue in the enzyme active site.

 

--> inactivates the enzymes and inhibits cross linking.

17

reactivity of B lactam system is due to...

highly strained 4-membered ring

18

NCC bind of the B lactam is compressed to ___ from _____

compressed to 90 from normal 120 angle

19

Bond angle of a tetrahedral carbon

109

20

Stress can be releived in beta lactam strain by conversion of...

carbonyl to the tetrahydral intermediate

21

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.

22

Penicillins assume a _____ structure with _____

folded ring structure with an sp3 hybridized nitrogen

23

There are many ____ which explains the heterogenecity of bacterial responses

penicillin binding proteins

24

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

25

Four mechanisms of resistance to beta-lactam

decreased cellular uptake

mutation of the PBPs

Presence of efflux pump

**Induction/elaboration of B-lactamases**

26

Four steps in B lactamase mechanism

[B lactamase + Penicillin] -->

Tetrahedral intermediate -->

Acylated B lactamase -->

[Regenerated enzyme + hydrolyzed penicillin]

27

Fast step in beta lactamase mechanism =

Hydrolysis of the acylated B-lactamase intermediate

28

__% of population has beta-lactam AB's

6-8%

29

How are beta lactams allergenic?

Drug acts as hapten - acylates host cell proteins

 

(generates covalent products that are "foreign")

30

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

31

Can you use other penicillin-type drug on a penicillin-allergic person?

NO!

32

____ tests for beta lactam allergy are recommended if there is doubt about allergy

Topical flare and wheal test

33

Main degradation products of Pen G

  1. Benzylpenicillenic acid
  2. Benzylpenicillic acid
  3. Benzylpenicilloic acid

34

Penicillin hydrolysis products have no _______

antibiotic activity

35

Hydrolysis of B lactam is ___

irreversible

(once the ring is opened, no closure)

36

Electronegative substituents have what effect when they're on the side chain carbonyl?

They reduce the nucleophilicity of the side chain amide carbonyl oxygen atom.

 

  • Stabilizes the penicillin against hydrolysis under acidic conditions
  • Increases oral bioavailability

37

Which is more stable, Pen G or Pen V?

Pen V is more stable to acid hydrolysis

 

*because the electronegativity of the ether oxygen decreases the nucleophilicity of the amide carbonyl

38

Solutions of penicillins should be used promptly and stored how?

In refrigerator at pH 6.0-6.8

39

_____ catalyze penicillin degradation

heavy metal ions

40

Penicillins with ______ are more highly protein bound

lipophilic side chains

41

Protein binding effects (2)

  1. Reduces BA
  2. Protects from degradation

42

Why isn't half life affected by protein binding?

dissociation rates from protein are fast,

and the renal excretion rates are the rate-limiting factor

43

Highest and lowest penicillins protein bound

cloxacillin = >90% protein bound

Ampicillin = 25-30% protein bound

44

Penicillin excretion routes

renal

biliary

45

Glomerular vs tubular filtration of penicillins

10% glomerular

90% Tubular

46

Effect of kidney disease on half life of penicillin

prolonged half life

47

Two mechanisms for tubular excretion

anionic

cationinc

48

Penicillins are anionic or cationic?

anionic.

Competition with probenecid (anion) for secretion when  coadministered with penicillin

49

Pen G

  1. a.k.a
  2. Spectrum
  3. Beta-lactamase sensitivity?
  4. Toxicity

  1. Benzylpenicillin
  2. Gram+ and N.gonorrhoeae and H. influenzae
  3. Yes, sensitive
  4. Acute allergy

50

Methicillin has no beta lactamase sensitivity because 

steric hindrance of nucleophilic attack by the enzyme on the beta lactam carbonyl. 

 

methoxy groups are attached ortho to the amide--hinder nucleophilic attack on the lactam.

51

Why must methicillin be injected?

Electron donation to the amide carbonyl oxygen by the methoxy groups = amide carbonyl oxygen more nucleophilic

 

= unstable in acidic conditions

52

Methicillin is mainly used for

B-lactamase producing S. Aureus

53

Methicillin is an effective...

inducer of beta lactamase

54

What causes MRSA to be methicillin resistant 

mutation in mecA in the penicillin binding protein gene (the protein is PBP2')

55

Cephapirin is a ___ AB

 

Structural difference?

cephalosporin

 

has a 6-membered sulfur containing ring instead of a 5 membered ring.

Some have an acetate in the 3 position = inactivated by hydrolysis by esterases (produces hydroxymethyl acid)

56

Ceph's MOA vs Pen MOA

same

57

Carbapenems are ______

carbon analogs of penicillins

58

Carbapenems have a ____ group instead of ____ that is present in penicillin's thiazolidine ring

methylene

sulfur

59

What does ring strain have to do with sulfur and carbapenems?

The methylene in Carbapenems instead of the sulfur causes increased ring strain because the methylene is smaller

60

2 things imipenem reacts with

PBP's

beta lactamases (inhibits them)

61

imipenem is hydrolyzed by _____

But this can be overcome by ___________

dehydropeptidase-1

coadministration of cilastatin (dehydropeptidase-1 inhibitor)

62

Imipenem and cilastatin is special because... (2)

it has broader spec than any other AB available

 

active against both gram + and -

63

imipenem and cilastatin are used to treat

Infections of:

GI, GU, Bone, Skin, and Endocardium 

64

ROA for imipenem-cilastatin

parenterally

65

Aztreonam disodium is a ____ drug that is inspired by _____

totally synthetic

monobactams

66

In Aztreonam, a _______ group takes the place of the c2 carboxyl group (as in pen/ceph)

sulfamic acid

67

Spectrum of Aztreonam

Almost all gram-

68

What (Aztreonam) property activates the beta lactam ring to hydrolysis and to reaction with PBP's?

The electronegativity of the sulfamic acid

69

Aztreonam is used to treat...

severe Gram- infections, especially those by penicillin-resistant organisms acquired in hospitals

70

Example of cross reactivity between pen and cephs

Ceftazidime

(has identical sidechain)