The Bacterial Cell Wall and Beta-Lactam Antibiotics

Question 1

Gram positive bacteria are ____ under a microscope (after staining)

Answer 1

Dark Purple

Question 2

Gram negative bacteria are ____ under a microscope (after staining)

Answer 2

Light Pink

Question 3

Describe a Gram positive cell wall

Answer 3

Peptidoglycan – lots of it Bacterial membrane underneath

Question 4

Describe a Gram negative cell wall

Answer 4

Outer envelope w/Porins Periplasmic space Less peptidoglycan Bacterial membrane

Question 5

Other name for Penicillin-binding proteins

Answer 5

Transpeptidases

Question 6

Difference in drug penetrance between G+ and G- bacteria

Answer 6

In G+ –> Drugs can penetrate outer layers of the wall effectively, membrane is main protective layer In G- –> Outer membrane excludes drugs, but some can still get in through porins in the outer membrane

Question 7

Difference in beta-lactamase secretions between G+ and G-

Answer 7

G+ –> excreted through the cell well to the external environment. Larger quantities produced G- –> Confined to periplasmic space

Question 8

Which type of bacteria has a thicker peptidoglycan layer

Answer 8

G+

Question 9

Which type of bacterial membrane is more lipoidal?

Answer 9

G-

Question 10

In G- bacteria, the peptidoglycan contains a ______ residue. In G+ this residue is replaced by a ______ residue.

Answer 10

Meso-diaminopimelic acid residue (DAP) L-lysine residue (COOH of DAP replaced by an H)

Question 11

Main components of peptidoglycan

Answer 11

N-acetylglucosamine and N-acetylmuramic acid

Question 12

In G- cells, peptidoglycan is cross linked by…

Answer 12

Bridge between DAP residue of one stand and the terminal D-Ala of the other

Question 13

In G+ cells, peptidoglycan is cross linked by…

Answer 13

L-Lys strand and the terminal D-Ala of the second molecule

Question 14

The cross link between peptidoglycan molecules typically consists of ___ amino acids

Answer 14

5 Ex. S. aureus has 5 glycines

Question 15

What happens in the transpeptidase reaction to connect S. aureus peptidoglycan

Answer 15

Since S. aureus is G+, The terminal glycine of one residue attaches to the penultimate Alanine residue, releasing the terminal D-Ala on the second molecule.

Question 16

beta-Lactam mechanism of action?

Answer 16

Inhibition of transpeptidases that glue the peptidoglycan strands together by cross linking

Question 17

beta-lactam antibiotics work by ______ the transpeptidase on the _____ residue

Answer 17

Acetylating Serine

Question 18

Following beta-lactam exposure, the bacterial cell wall…

Answer 18

is subject to cell lysis and cell death

Question 19

The beta-lactam system is very reactive due to steric strain. The NCC bond angle is a ____ angle, compared to the normal _____ angle.

Answer 19

90 degree 120 degree

Question 20

Aside from steric strain, the beta-lactam carbonyl is also more reactive due to….

Answer 20

its poor stereoelectronics. These make it more like a ketone carbonyl than an aminde carbonyl due to the overlap on non-bonded electrons. In Bryan words – to make the Nitrogen’s electrons fit with the C=O, they have to fold up in a weird shape that inhibits their ability to have resonance. Makes it more ketone-like

Question 21

Penicillins assume what structure

Answer 21

Folded ring with sp3 hybridized Nitrogen

Question 22

Why don’t bacterial transpeptidases catalyze reactions with host cell proeins?

Answer 22

The bacterial substrate contain D-Ala amino acid residue not found in host cell proteins

Question 23

Causes of beta-lactam resistance

Answer 23

Decreased cellular uptake of drug Mutation of Pen-binding proteins Presence of an Efflux pump Induction/Elaboration of bacterial beta-lactamases

Question 24

What do beta-lactamases do?

Answer 24

Catalyze the hydrolysis of the beta-lactam moiety

Question 25

Difference between the chemical reaction of a beta-lactam+transpeptidase and the reaction of a beta-lactam and beta-lactamase

Answer 25

Basically nothing except the beta-lactamases are recyclable

Question 26

T or F. Resistance to beta-lactams is uncommon.

Answer 26

False. It is increasingly common

Question 27

Describe the speed of the hydrolysis of the acetylated intermediate

Answer 27

Its fast, so the enzyme can hydrolyze many drug molecules rapidly

Question 28

About \_\_\_% of the US population is allergic to beta-lactams

Answer 28

6-8

Question 29

Cause of the allergenicity of beta-lactams

Answer 29

The drug acts as a hapten It acetylates host cell proteins, which then raise Abs

Question 30

Why can't the drug be modified to cause no allergic reaction

Answer 30

The site that causes the allergy is also the one that causes the antimicrobial fxn

Question 31

Can a person who has demonstrated a penicillin allergy of one kind be given a different type of penicillin to avoid allergic response.

Answer 31

No. No they cannot.

Question 32

Recommendations for patients that are unsure about allergy status?

Answer 32

Topical flare and wheal test for beta-lactam allergy

Question 33

Under acidic conditions (the stomach), the main degradation products of Pen G are...

Answer 33

BenzylpenicILLENIC Acid BenzylpenILLIC Acid BenzylpenicILLOIC Acid

Question 34

How is penicillenic acid made in acidic degradation.

Answer 34

Beta-elimination of sulfhydryl group in the second penicillin break down intermediate

Question 35

How much antibiotic activity is retained by penicillin hydrolysis products

Answer 35

No antibiotic activity

Question 36

T or F. Hydrolysis of the beta-lactam is irreversible.

Answer 36

True. Once the ring has been opened, it can't be pushed back shut

Question 37

Significance of electronegative substituents on the side chain carbonyl. How does that work.

Answer 37

Electronegative substituents on the side chain carbonyl reduce the nucleophilicity of the side chain amide carbonyl oxygen atom. This stabilizes the penicillin against hydrolsis under acidic conditions and increased bioavailability.

Question 38

Give an example of a Penicillin made more stable by addition of an electronegative group

Answer 38

Penicillin G is 80% hydrolyzed in te stomach An extra Oxygen makes Penicillin V 35% hydrolyzed in the stomach.

Question 39

Storage and longevity of penicillin solutions.

Answer 39

They should be used promptly (if being used parenterally) Store in fridge btw pH 6-6.8

Question 40

\_\_\_\_\_ catalyze penicillin degradation reactions and should be kept away from solutions

Answer 40

Heavy metal ions

Question 41

What makes certain penicillins more able to bind serum proteins more effectively.

Answer 41

More lipophilic side chains

Question 42

Pro of serum protein binding

Answer 42

In general, it protects drugs from degradation

Question 43

Serum protein binding _____ the bioavailability. Why?

Answer 43

Reduces Reduces effective concentration of free drug.

Question 44

Why aren't penicillin half lives altered by protein binding?

Answer 44

Their dissociation rates from the protein are fast and the renal excretion rates are rate limiting

Question 45

\_\_\_% of penicillin renal excretion is performed by glomerular filtration. \_\_\_\_\_% by tubular secretion.

Answer 45

10% 90%

Question 46

Relationship of Probenecid and Penicillin

Answer 46

Porbenecid is an anion administered with penicillin that will compete with penicillin for secretion, increasing the half life of penicillin.

Question 47

Antimicrobial spectrum for Benzylpenicillin (Pen G)

Answer 47

G+ N. gonorrhoeae + H. influenza

Question 48

Is Benzylpenicillin (Pen G) sensitive to beta-lactamase?

Answer 48

yes

Question 49

How is Benzylpenicillin (Pen G) administered?

Answer 49

Orally in large doses (due to stomach acid) Most effective parenteral

Question 50

Toxicity associated with Benzylpenicillin (Pen G)?

Answer 50

Acute Allergic Reactions

Question 51

Precautions for Benzylpenicillin (Pen G)

Answer 51

Patients with significant allergy/asthma history

Question 52

Methicillin. Beta-lactamase sensitive?

Answer 52

No Steric hindrance of the nucleophilic attack by the enzyme on the beta-lactam carbonyl

Question 53

Removal of one Methicillin methoxyl group (or a change to para position) will cause...

Answer 53

Abolished beta-lactamase sensitivity

Question 54

How is Methicillin administered?

Answer 54

By injection Unstable to acid in the stomach due to electron donation toward the added o-methoxy groups

Question 55

Antimicrobial spectrum of Methicillin?

Answer 55

beta-lactamase producing S. aureus

Question 56

Why should Methicillin only be used when required

Answer 56

It induces beta-lactamase production, making other penicillins less effective

Question 57

How does MRSA avoid Methicillin?

Answer 57

Mutation in a transpeptidase Methicillin resistance gene (mecA) and Penicillin binding protein (PBP2)

Question 58

Cephapirin is what type of antibiotic

Answer 58

Cephalosporin

Question 59

What is fused to the beta lactam in Cephapirin

Answer 59

A six-membered sulfur containing ring (instead of the boring 5 member one)

Question 60

Cephalosporins with have an acetate in the 3-position are...

Answer 60

metabolically inactivated by hydrolysis by host esterases Makes hydroxymethyl acid that lactonizes

Question 61

What are carbapenems?

Answer 61

Carbon analogs of penicillins Sulfur group in thiazolide ring of penicillins becomes methylene

Question 62

Imipenem. beta lactamase sensitivity?

Answer 62

Reacts with an inhibits beta-lactamases

Question 63

Imipenem is hydrolyzed by.... How to get around it?

Answer 63

Renal dihydropeptidase-1 Cilastatin (a dihydropeptidase inhibitor)

Question 64

Perks of Imipenem + Cilastatin

Answer 64

Broader spectrum of antibiotic activity than anything else in US Gram + and Gram - "Magic Bullets"

Question 65

Why is Imipenem + Cilastatin restricted?

Answer 65

To avoid bacterial resistance

Question 66

Imipenem + Cilastatin is typically used to treat...

Answer 66

Serious gut infections, GU, Bone, Skin, and Endocardium

Question 67

Imipenem + Cilastatin route of administration

Answer 67

Parenterally

Question 68

Aztreonam is completely synthetic, but inspired by...

Answer 68

monocyclic beta-lactams (monobactams

Question 69

In Aztreonam, the C2 carboxyl group is replaced with

Answer 69

Sulfamic Acid

Question 70

Aztreonam antibiotic spectrum.

Answer 70

Almost entirely G-

Question 71

What makes Aztreonam so good anyway?

Answer 71

The Sulfamic Acid activates the beta-lactam ring toward hydrolysis and to rxn with penicillin binding proteins

Question 72

Indication for Aztreonam?

Answer 72

Severe G- Infections, especially with penicillin-resistant hospital organisms.

Question 73

Cross allergenicity with penicillins and cephalosporins...is it a thing?

Answer 73

No (except for Ceftazidime)

Question 74

Identify

Answer 74

Benzylpenicillin

Question 75

Identify.

Answer 75

Methicillin

Question 76

Identify.

Answer 76

Cephaprin

Question 77

Identify.

Answer 77

Imipenem

Question 78

Identify.

Answer 78

Aztreonam