Drug Development and Penicillins Quiz

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Questions and Answers

What is the main aim of drug development for staphylococci?

To improve chemical stability for oral administration (correct)

To enhance resistance to antibiotic efflux pumps

To increase the effectiveness of the immune response

To decrease the range of activity against other bacteria

Which structural component is essential for the binding of penicillins?

Amide group (correct)

Hydroxyl group

Aromatic ring

Bicyclic system

What role does the b-lactam ring play in the mechanism of action of penicillins?

It facilitates the degradation of the bacterial cell wall

It covalently links to the enzyme’s active site leading to irreversible inhibition (correct)

It modifies the structure of the antibiotics to prevent bacterial resistance

It enhances the immune response against bacteria

Why is the bicyclic system important in the development of b-lactams?

It increases b-lactam ring strain Signup and view all the answers

Which statement accurately describes the variations possible in the structure of b-lactams?

Variations are restricted to the side chain (R) Signup and view all the answers

What compounds are notably transformed by gastric acid in penicillins?

Penicilloic acids Signup and view all the answers

Which enzyme is responsible for degrading penicillins?

Penicillinase Signup and view all the answers

What is a characteristic of oxacillin and its derivatives?

Less active than other penicillins. Signup and view all the answers

Which of the following statements about the side chains in penicillins is true?

Hydrophilic groups at the α-position increase activity against Gram-negative bacteria. Signup and view all the answers

What is the pH level of gastric acid that affects the transformation of penicillins?

2 Signup and view all the answers

Which structure represents an ester group in the context of the provided content?

R-CO-OR Signup and view all the answers

What role does the nature of R and R’ groups play in penicillin derivatives?

They affect absorption and plasma protein binding. Signup and view all the answers

What can penicilloic acid readily decarboxylate to form?

Penilloic acid Signup and view all the answers

What is the effect of increasing hydrophobicity in penicillin side chains?

Has little effect on Gram-positive activity but lowers Gram-negative activity. Signup and view all the answers

Which functional group is associated with NH2OH in the context provided?

Hydroxamic acid Signup and view all the answers

Which factors contribute to the range of antibiotic activity?

Presence of b-lactamases and efflux mechanisms. Signup and view all the answers

The presence of which element in the structure contributes to the classification of a compound as thioester?

Sulfur (S) Signup and view all the answers

Why are some antibiotics orally inactive?

They are broken down by stomach acid. Signup and view all the answers

What is formed from the reaction of penicillins with acidified sodium salts?

Penilloic acid Signup and view all the answers

What type of bacteria are oxacillin and its derivatives primarily active against?

Staphylococcus aureus. Signup and view all the answers

Which Gram-negative species is NOT indicated as sensitive to carbenicillin?

Staphylococcus Signup and view all the answers

What characteristic of the prodrugs of ampicillin improves their efficacy?

Increased cell membrane permeability Signup and view all the answers

How does the introduction of an ionized group in penicillins affect its activity?

It confers activity against Gram-negative bacilli. Signup and view all the answers

What is a common characteristic of a compound like R-COOH?

It is a carboxylic acid. Signup and view all the answers

What is the main function of the ester in the prodrugs of ampicillin?

To mask the polar carboxylic acid group Signup and view all the answers

What would be a likely effect of penicillinase on penicillins?

Degrade the antibiotic. Signup and view all the answers

Which of the following compounds acts as a prodrug for carbenicillin?

Carfecillin Signup and view all the answers

What role does the bulky penicillin nucleus play in the prodrug activation process?

It acts as a steric shield for the methyl ester. Signup and view all the answers

Which of the following correctly describes a characteristic of bacampicillin?

It is metabolised to yield the active free drug. Signup and view all the answers

What happens to the hydrolysed product of the extended ester during drug metabolism?

It degrades and loses efficacy. Signup and view all the answers

Carbenicillin has broader activity against Gram-negative bacteria than which of the following antibiotics?

Ampicillin Signup and view all the answers

Which of the following statements is true regarding the metabolism of methyl ester of ampicillin?

It remains unhydrolysed in the body. Signup and view all the answers

What chemical group largely determines the classification of carbenicillin as a carboxypenicillin?

Carboxylic acid group Signup and view all the answers

What is a primary reason for the limited success of combinations involving β-lactamase-resistant and β-lactamase-sensitive penicillins?

Inability of β-lactamase-sensitive penicillins to penetrate cell walls Signup and view all the answers

What role does clavulanic acid play in the context of β-lactam combination therapy?

It acts as a mechanism-based inhibitor of β-lactamases Signup and view all the answers

Why are free acids of most penicillins unsuitable for oral or parenteral administration?

They are not soluble in water. Signup and view all the answers

What are salts of penicillins combined with organic bases like benzathine primarily used for?

Providing effective blood levels over a prolonged period Signup and view all the answers

Which classification of penicillins indicates that they have been modified from their natural state?

Semisynthetic penicillins Signup and view all the answers

What characterizes the acid resistance of most penicillins?

Most penicillins are weak acids with specific pKa values. Signup and view all the answers

Which type of penicillin is specifically known for being resistant to β-lactamases?

Semisynthetic penicillin Signup and view all the answers

What type of spectrum of activity do penicillins have based on their classification?

Narrow, intermediate, broad, or extended spectrum Signup and view all the answers

What is the primary action of penicillin regarding bacterial cell wall synthesis?

Inhibiting transpeptidase activity Signup and view all the answers

Which structure does penicillin mimic to inhibit bacterial cell wall synthesis?

D-Ala-D-Ala Signup and view all the answers

Why are Gram +ve bacteria more susceptible to penicillins compared to Gram -ve bacteria?

They lack a hydrophobic barrier Signup and view all the answers

What role do porins play in the resistance of Gram -ve bacteria to penicillins?

Preventing the action of penicillin Signup and view all the answers

What is one characteristic of Gram -ve bacteria that contributes to their resistance to penicillin?

Presence of lactamase enzymes Signup and view all the answers

What structural feature of penicillin makes it an effective inhibitor of bacterial cell wall synthesis?

Acyl side chain similar to D-Ala Signup and view all the answers

Why is 6-methylpenicillin considered inactive despite its structural similarity to penicillin?

It cannot bind to transpeptidase Signup and view all the answers

How does the thickness of the cell wall impact the effectiveness of penicillin on Gram +ve bacteria?

Thicker walls do not form a barrier to penicillin Signup and view all the answers

In what way does penicillin act as an 'umbrella' inhibitor?

It irreversibly binds to bacterial enzymes Signup and view all the answers

What composition of Gram -ve cell walls contributes to their overall resistance to penicillins?

Hydrophobic outer membrane Signup and view all the answers

Which of the following statements is true regarding the way penicillin affects bacteria?

Penicillin disrupts cell wall synthesis Signup and view all the answers

What is a significant factor limiting the effectiveness of penicillin due to bacterial adaptation?

High levels of transpeptidase enzyme Signup and view all the answers

What role does the peptidoglycan layer have in bacterial susceptibility to antibiotics?

Is the main target for penicillin Signup and view all the answers

Study Notes

Antibiotics

Waksman proposed a definition of antibiotics in 1942 as substances produced by microorganisms that inhibit or destroy other microorganisms (bacteria, mycobacteria, fungi, protozoa, or viruses).
Benedict and Langlykke defined antibiotics in 1947 as chemical compounds derived from living organisms that inhibit the life processes of microorganisms at low concentrations.
Modern antibiotics may include synthesized compounds.
Antibiotics are specific chemicals derived from living organisms or synthesized as structural analogs, inhibiting other microorganisms.

Classification of Antibiotics

A substance is classified as an antibiotic if it fulfills four conditions:
- It is a product of metabolism or duplicated from a chemical synthesis.
- It is synthesized as a structural analog of an antibiotic.
- It antagonizes the growth or survival of one or more species of microorganisms.
- It is effective in low concentrations.

Penicillins

Penicillins are antibacterial agents that inhibit bacterial cell wall synthesis.
Discovered by Sir Alexander Fleming in 1928 from a fungal colony.
Isolated and purified by Florey, Chain, and Abraham at Oxford University (1938).
First successful clinical trial conducted in 1941.
Produced by large-scale fermentation (1944).
Chemical structure elucidated via X-ray crystallography (1945).
Full chemical synthesis developed by Sheehan in 1957.
Development of semi-synthetic penicillins (1958-60) along with the discovery of clavulanic acid and beta-lactamase inhibitors.

Structure of Penicillins

The penam ring is composed of a cysteine and a valine residue.
The Beta-lactam ring and the thiazolidine ring are not coplanar but are folded, with an angle of 117°.
This non-planarity suppresses normal amide resonance.
The unshared electrons are far to interact with resonance.
The beta-lactam ring is highly reactive and unstable.

Mechanism of Action

Penicillins inhibit the bacterial enzyme transpeptidase, crucial for bacterial cell wall synthesis.
Penicillins acylate bacterial D-transpeptidase, forming a covalent bond to the enzyme's active site, leading to irreversible inhibition.
The beta-lactam ring plays a key role in the inhibition mechanism.
Penicillin blocks the final cross-linking stage of cell wall synthesis by reacting with transpeptidase.

Resistance to Penicillins

Gram-negative bacteria have an outer membrane that prevents penicillin access.
Penicillins can only cross the outer membrane via porins.
High levels of transpeptidases and the presence of beta-lactamases in the periplasmic space contribute to penicillin resistance.
Mutations and efflux mechanisms also contribute to resistance.

Penicillin Analogues

Penicillin analogs are prepared through fermentation and total synthesis, with limited yields from total synthesis.
By varying the carboxylic acid in the fermentation medium and employing total synthesis.
Semi-synthetic procedures use naturally occurring structures as starting materials for analog synthesis.

Problems with Penicillin G

Sensitivity to stomach acids.
Sensitivity to beta-lactamases.
Limited range of activity.

Range of Activity

Hydrophobic side chains lead to high activity against Gram-positive bacteria and low activity against Gram-negative bacteria.
Hydrophilic side chains increase activity against Gram-negative bacteria.
Introduction of certain groups to increase activity and range.
Prodrugs like those formed for ampicillin have increased cell membrane permeability and polar carboxylic acid groups masked by ester groups, improving oral and parenteral activity, allowing longer action.

Beta-Lactamase Inhibitors

The strategy of using beta-lactamase inhibitors in combination with beta-lactamase-sensitive penicillins, although promising, has been limited.
Factors that contribute to this failure include the lipophilic nature of penicillinase-resistant penicillins, the reversible binding to the beta-lactamase, the induction of beta-lactamases, and poor penetration.
Discovery of clavulanic acid (a naturally occurring inhibitor) has enabled renewed interest in penicillin combination therapies.

Chemical Properties of Penicillins

Most penicillins are acidic with pKa values between 2.5 to 3.0.
The free acid form isn't suitable for oral administration.
The sodium and potassium salts are more soluble in water and readily absorbed through oral and parenteral administration.
Some salts of penicillins with organic bases, e.g., benzathine, procaine, and hydrabamine, have limited water solubility, acting as depot forms for long-term drug delivery.

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Description

Test your knowledge on drug development specifically focused on staphylococci and the structural components essential for penicillin functionality. This quiz covers the mechanism of action, variations in b-lactams, and the chemistry of penicillin derivatives.