9 & 10 - Medicinal Chemistry of Beta-Lactam Antibiotics Flashcards
What is AMR?
AMR stands for Antimicrobial Resistance, which is one of the fastest evolving threats to global health.
What historical event led to the discovery of penicillin?
In 1928, Alexander Fleming observed zones of inhibition around Penicillium notatum in a culture of Staphylococcus aureus.
What are the estimated annual deaths due to resistant infections in the USA according to the CDC (2019)?
35,000 deaths annually.
What is the predicted annual death figure from resistant infections by 2050 if no action is taken?
Over 10 million deaths.
What are the main classes of beta-lactamase enzymes?
Classes A, B, C, and D.
What are the two main strategies used to combat β-lactam resistance?
- Development of new β-lactam antibiotics with improved stability
- Co-administration of β-lactam antibiotics with a β-lactamase inhibitor.
What was the contribution of beta-lactams to the global antibiotics market in 2022?
$28 billion.
What is the structure of penicillin G?
Penicillin G is a benzylpenicillin with a specific chemical structure.
What is the key feature of the β-lactam ring that contributes to penicillin’s biological action?
The strained β-lactam ring is key to its high chemical reactivity.
What is peptidoglycan?
A composite structure in bacterial cell walls made of carbohydrate backbones and peptide chains.
What is the mechanism of action of penicillins and cephalosporins?
They inhibit transpeptidases, preventing the cross-linking of peptide chains in peptidoglycan.
True or False: β-lactams are effective against both Gram-positive and Gram-negative bacteria.
True.
Fill in the blank: Clavulanic acid is a _______ that acts as a β-lactamase inhibitor.
clavam.
What is the significance of thienamycin in the development of carbapenems?
Thienamycin is a potent broad-spectrum antibiotic but was unsuitable for clinical use due to instability.
What is the role of cilastatin in carbapenem administration (Primaxin)? What is Meropenem?
Cilastatin is a dehydropeptidase inhibitor co-administered with imipenem.
What is the expected growth of the global antibiotics market by 2030?
$68.04 billion.
What is a common property of injectable β-lactams?
They have poor oral absorption, necessitating parenteral administration.
What are the carbohydrate units that make up peptidoglycan?
- N-acetylglucosamine (NAG)
- N-acetylmuramic acid (NAM).
What is a notable characteristic of meropenem compared to imipenem?
Meropenem has good stability to dehydropeptidase and does not require coadministration with cilastatin.
What type of antibiotic activity can β-lactams exhibit?
- Bacteriocidal: cell lysis or rupture
- Bacteriostatic: cell remains intact but cannot reproduce.
What does AMR stand for in the context of medicinal chemistry?
Antimicrobial Resistance
AMR poses significant challenges in treating bacterial infections.
Who discovered penicillin?
Alexander Fleming
Fleming’s discovery in 1928 marked the beginning of modern antibiotics.
What is the basic structure of penicillin?
β-lactam ring
The β-lactam ring is crucial for its antibacterial activity.
What are the types of β-lactam antibiotics?
Penicillins and Cephalosporins
Carbapenems are also included in the β-lactam class.
What is the mechanism of action for β-lactam antibiotics?
Inhibition of transpeptidases
This inhibition disrupts bacterial cell wall synthesis.
What enzyme is used to prepare 6-APA from penicillin G?
Penicillin acylase
This enzyme does not affect the β-lactam amide bond.
What are semisynthetic penicillin analogues?
Compounds made by modifying the penicillin nucleus
These analogues can offer improved efficacy or spectrum of activity.
What is the significance of clavulanic acid in antibiotic therapy?
It is a β-lactamase inhibitor
Clavulanic acid is often combined with amoxicillin to enhance efficacy.
What is the most common mechanism of resistance to β-lactams?
Production of β-lactamases
β-lactamases inactivate the antibiotic before it can act on its target.
True or False: Cephalosporins are generally resistant to staphylococcal β-lactamase.
True
This resistance varies among different β-lactam antibiotics.
What are the two structural features that can enhance stability against β-lactamases?
- Appropriate side-chain geometry
- Presence of a 6α(7α)-substituent
These modifications can improve the effectiveness of the antibiotic.
Fill in the blank: Augmentin is a combination of _______ and _______.
Amoxicillin, Clavulanic acid
This combination is widely used for its broad spectrum of activity.
What are the newer β-lactamase inhibitors mentioned?
- Sulbactam
- Avibactam
- Vaborbactam
These inhibitors are used in combination with various antibiotics to combat resistance.
What is the biosynthesis hypothesis for penicillins?
Arnstein tripeptide hypothesis
This hypothesis suggests that penicillins are synthesized from three amino acids.
What is the role of the enzyme IPNS in the biosynthesis of penicillins?
It catalyzes the formation of the β-lactam ring
IPNS requires Fe2+, O2, and ascorbate for its activity.
What happens to β-lactams in acidic conditions?
They can cyclize to form oxazolones
This cyclization generally leads to reduced bioavailability.
What is a common feature of semisynthetic cephalosporins?
Thiazole unit
This unit is often included in their structure to enhance activity.
What is the main therapeutic use of ceftriaxone?
Treatment of serious bacterial infections
It is a third-generation cephalosporin with broad-spectrum activity.
What is Flucloxacillin used for?
Useful against topical infections and S. aureus
Flucloxacillin is a beta-lactam antibiotic effective against certain bacterial infections.
What is Augmentin composed of?
Amoxycillin plus clavulanic acid
Augmentin is a commonly prescribed antibiotic that combines two active ingredients to enhance efficacy.
What are third-generation cephalosporins restricted to?
Hospital use
This restriction aims to minimize the risk of spreading antibiotic resistance.
What is a major contributing factor to resistance problems related to beta-lactam antibiotics?
Widespread use or abuse of penicillins for unsuitable infections
Inappropriate prescribing practices can lead to increased resistance.
What is Methicillin-resistant Staphylococcus aureus (MRSA)?
A Gram+ve organism not tractable by any beta-lactam antibiotic
MRSA poses a significant clinical challenge due to its resistance.
How does MRSA arise?
From mutation of the target transpeptidase enzymes
This mutation allows MRSA to evade the effects of beta-lactam antibiotics.
What are glycopeptides, and which is notably effective against MRSA?
Notably vancomycin
Glycopeptides work by inhibiting cell wall biosynthesis in bacteria.
What type of bonding network forms between vancomycin and the peptidoglycan terminal tripeptide?
An extended H-bonding network
This interaction is crucial for the antibiotic’s mechanism of action.
What is the mutation leading to vancomycin-resistant Staphylococcus aureus (VRSA)?
D-Ala-D-Ala to D-Ala-D-lactate
Resistance is developed by mutation of the petidoglycan dipeptide terminus.
This mutation alters the target of vancomycin, contributing to antibiotic resistance.
Describe the ring opening process for cephalosporins.
Describe the MOA for penicillins and cephalosporins.
What is the MOA for Beta-lactams?
Describe the steps and mechanisms by which penicillin is converted to cephalosporin, using MCPBA.
How does clavulanic acid inhibit Beta-lactamase?
Building off clavulanic acid, what are examples of extended spectrum Beta-lactamase inhibitors?
What is the MOA of Avibactam?
What is the MOA of Vaborbactam?
How do Beta-lactams form A penicilloic acid via Oxazolone intermediate? How is this combated against?
How are Penicillins and Cephalosporins biosynthesised via a transient thioaldehyde derivative?
How is Cephalosporin synthesised from a bromomethyl penicillin derivative? (Hint - radial)
