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CHEM335 (GN) > 9 & 10 - Medicinal Chemistry of Beta-Lactam Antibiotics > Flashcards

9 & 10 - Medicinal Chemistry of Beta-Lactam Antibiotics Flashcards

1
Q

What is AMR?

A

AMR stands for Antimicrobial Resistance, which is one of the fastest evolving threats to global health.

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2
Q

What historical event led to the discovery of penicillin?

A

In 1928, Alexander Fleming observed zones of inhibition around Penicillium notatum in a culture of Staphylococcus aureus.

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3
Q

What are the estimated annual deaths due to resistant infections in the USA according to the CDC (2019)?

A

35,000 deaths annually.

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4
Q

What is the predicted annual death figure from resistant infections by 2050 if no action is taken?

A

Over 10 million deaths.

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5
Q

What are the main classes of beta-lactamase enzymes?

A

Classes A, B, C, and D.

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6
Q

What are the two main strategies used to combat β-lactam resistance?

A
  • Development of new β-lactam antibiotics with improved stability
  • Co-administration of β-lactam antibiotics with a β-lactamase inhibitor.
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7
Q

What was the contribution of beta-lactams to the global antibiotics market in 2022?

A

$28 billion.

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8
Q

What is the structure of penicillin G?

A

Penicillin G is a benzylpenicillin with a specific chemical structure.

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9
Q

What is the key feature of the β-lactam ring that contributes to penicillin’s biological action?

A

The strained β-lactam ring is key to its high chemical reactivity.

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10
Q

What is peptidoglycan?

A

A composite structure in bacterial cell walls made of carbohydrate backbones and peptide chains.

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11
Q

What is the mechanism of action of penicillins and cephalosporins?

A

They inhibit transpeptidases, preventing the cross-linking of peptide chains in peptidoglycan.

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12
Q

True or False: β-lactams are effective against both Gram-positive and Gram-negative bacteria.

A

True.

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13
Q

Fill in the blank: Clavulanic acid is a _______ that acts as a β-lactamase inhibitor.

A

clavam.

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14
Q

What is the significance of thienamycin in the development of carbapenems?

A

Thienamycin is a potent broad-spectrum antibiotic but was unsuitable for clinical use due to instability.

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15
Q

What is the role of cilastatin in carbapenem administration (Primaxin)? What is Meropenem?

A

Cilastatin is a dehydropeptidase inhibitor co-administered with imipenem.

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16
Q

What is the expected growth of the global antibiotics market by 2030?

A

$68.04 billion.

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17
Q

What is a common property of injectable β-lactams?

A

They have poor oral absorption, necessitating parenteral administration.

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18
Q

What are the carbohydrate units that make up peptidoglycan?

A
  • N-acetylglucosamine (NAG)
  • N-acetylmuramic acid (NAM).
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19
Q

What is a notable characteristic of meropenem compared to imipenem?

A

Meropenem has good stability to dehydropeptidase and does not require coadministration with cilastatin.

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20
Q

What type of antibiotic activity can β-lactams exhibit?

A
  • Bacteriocidal: cell lysis or rupture
  • Bacteriostatic: cell remains intact but cannot reproduce.
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21
Q

What does AMR stand for in the context of medicinal chemistry?

A

Antimicrobial Resistance

AMR poses significant challenges in treating bacterial infections.

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22
Q

Who discovered penicillin?

A

Alexander Fleming

Fleming’s discovery in 1928 marked the beginning of modern antibiotics.

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23
Q

What is the basic structure of penicillin?

A

β-lactam ring

The β-lactam ring is crucial for its antibacterial activity.

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24
Q

What are the types of β-lactam antibiotics?

A

Penicillins and Cephalosporins

Carbapenems are also included in the β-lactam class.

25
Q

What is the mechanism of action for β-lactam antibiotics?

A

Inhibition of transpeptidases

This inhibition disrupts bacterial cell wall synthesis.

26
Q

What enzyme is used to prepare 6-APA from penicillin G?

A

Penicillin acylase

This enzyme does not affect the β-lactam amide bond.

27
Q

What are semisynthetic penicillin analogues?

A

Compounds made by modifying the penicillin nucleus

These analogues can offer improved efficacy or spectrum of activity.

28
Q

What is the significance of clavulanic acid in antibiotic therapy?

A

It is a β-lactamase inhibitor

Clavulanic acid is often combined with amoxicillin to enhance efficacy.

29
Q

What is the most common mechanism of resistance to β-lactams?

A

Production of β-lactamases

β-lactamases inactivate the antibiotic before it can act on its target.

30
Q

True or False: Cephalosporins are generally resistant to staphylococcal β-lactamase.

A

True

This resistance varies among different β-lactam antibiotics.

31
Q

What are the two structural features that can enhance stability against β-lactamases?

A
  • Appropriate side-chain geometry
  • Presence of a 6α(7α)-substituent

These modifications can improve the effectiveness of the antibiotic.

32
Q

Fill in the blank: Augmentin is a combination of _______ and _______.

A

Amoxicillin, Clavulanic acid

This combination is widely used for its broad spectrum of activity.

33
Q

What are the newer β-lactamase inhibitors mentioned?

A
  • Sulbactam
  • Avibactam
  • Vaborbactam

These inhibitors are used in combination with various antibiotics to combat resistance.

34
Q

What is the biosynthesis hypothesis for penicillins?

A

Arnstein tripeptide hypothesis

This hypothesis suggests that penicillins are synthesized from three amino acids.

35
Q

What is the role of the enzyme IPNS in the biosynthesis of penicillins?

A

It catalyzes the formation of the β-lactam ring

IPNS requires Fe2+, O2, and ascorbate for its activity.

36
Q

What happens to β-lactams in acidic conditions?

A

They can cyclize to form oxazolones

This cyclization generally leads to reduced bioavailability.

37
Q

What is a common feature of semisynthetic cephalosporins?

A

Thiazole unit

This unit is often included in their structure to enhance activity.

38
Q

What is the main therapeutic use of ceftriaxone?

A

Treatment of serious bacterial infections

It is a third-generation cephalosporin with broad-spectrum activity.

39
Q

What is Flucloxacillin used for?

A

Useful against topical infections and S. aureus

Flucloxacillin is a beta-lactam antibiotic effective against certain bacterial infections.

40
Q

What is Augmentin composed of?

A

Amoxycillin plus clavulanic acid

Augmentin is a commonly prescribed antibiotic that combines two active ingredients to enhance efficacy.

41
Q

What are third-generation cephalosporins restricted to?

A

Hospital use

This restriction aims to minimize the risk of spreading antibiotic resistance.

42
Q

What is a major contributing factor to resistance problems related to beta-lactam antibiotics?

A

Widespread use or abuse of penicillins for unsuitable infections

Inappropriate prescribing practices can lead to increased resistance.

43
Q

What is Methicillin-resistant Staphylococcus aureus (MRSA)?

A

A Gram+ve organism not tractable by any beta-lactam antibiotic

MRSA poses a significant clinical challenge due to its resistance.

44
Q

How does MRSA arise?

A

From mutation of the target transpeptidase enzymes

This mutation allows MRSA to evade the effects of beta-lactam antibiotics.

45
Q

What are glycopeptides, and which is notably effective against MRSA?

A

Notably vancomycin

Glycopeptides work by inhibiting cell wall biosynthesis in bacteria.

46
Q

What type of bonding network forms between vancomycin and the peptidoglycan terminal tripeptide?

A

An extended H-bonding network

This interaction is crucial for the antibiotic’s mechanism of action.

47
Q

What is the mutation leading to vancomycin-resistant Staphylococcus aureus (VRSA)?

A

D-Ala-D-Ala to D-Ala-D-lactate

This mutation alters the target of vancomycin, contributing to antibiotic resistance.

48
Q

Describe the ring opening process for cephalosporins.

A
49
Q

Describe the MOA for penicillins and cephalosporins.

A
50
Q

What is the MOA for Beta-lactams?

A
51
Q

Describe the steps and mechanisms by which penicillin is converted to cephalosporin, using MCPBA.

A
52
Q
A
53
Q

How does clavulanic acid inhibit Beta-lactamase?

A
54
Q

Building off clavulanic acid, what are examples of extended spectrum Beta-lactamase inhibitors?

A
55
Q

What is the MOA of Avibactam?

A
56
Q

What is the MOA of Vaborbactam?

A
57
Q

How do Beta-lactams form A penicilloic acid via Oxazolone intermediate? How is this combated against?

A
58
Q

How are Penicillins and Cephalosporins biosynthesised via a transient thioaldehyde derivative?

A
59
Q

How is Cephalosporin synthesised from a bromomethyl penicillin derivative? (Hint - radial)

A

CHEM335 (GN) (4 decks)

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