Antimicrobial drugs Flashcards
Describe the discovery and mechanism of action of sulphonamide drugs which selectively target bacterial enzymes catalysis impending bacterial growth.
Biochemical pathway utilised by bacteria to synthesise tetrahydrofolate provides a one
carbon unit for pyrimidine bases
* If this pathway is impeded bacterial DNA synthesis stops
* Sulphonamides inhibit this pathway by acting as a mimic for p-amino benzoic acid (PABA)
* The bacterial dihydropteroate synthesise accepts the sulphonamide into the active site,
once bound it prevents PABA from binding
* Dihydropteroate is competitively inhibited
PABA –> Dihydrofolate –> tetrahydrofolate –> Nucleic Acids
Higher animals and mammalians synthesise tetrahydrofolate from folic acid (obtained from
diet) using a different pathway
* Folic acid is carried across animal cell membrane by transport proteins.
* Mammalian cell lack the enzyme dihydropteroate synthesise and are unaffected by
sulphonamides
* Sulphonamides inhibit bacterial growth, they do not kill the pathogens, they prevent them
from multiplying
* Body defence hunter-killer CD8 cells eliminate the invaders
* Bacteriostatic
* Useful for treating infections of the eyes, mucosal membranes, GIT and urinary tract
Describe the mechanism of action of β-lactam antibiotics
β-lactam antibiotics inhibit bacterial cell wall synthesis.
The bacterial cell wall is composed of peptidoglycan, which is a complex network of sugars and amino acids.
β-lactam antibiotics contain a β-lactam ring, which mimics the structure of the D-alanyl-D-alanine peptide in the peptidoglycan cell wall.
β-lactam antibiotics irreversibly bind to and inhibit the activity of transpeptidases, which are enzymes that catalyze the final step in the synthesis of the peptidoglycan cell wall.
The inhibition of transpeptidases leads to the formation of weak points in the peptidoglycan cell wall, making the bacterial cell vulnerable to osmotic pressure.
The bacterial cell eventually undergoes lysis and death due to the increased osmotic pressure.
The inhibition of transpeptidases also prevents the formation of new peptidoglycan, leading to impaired bacterial cell growth and replication.
The mechanism of action of β-lactam antibiotics is selective for bacterial cells as the peptidoglycan cell wall is unique to bacteria and not present in human cells.
This selectivity allows β-lactam antibiotics to effectively target bacterial infections while minimizing harm to human cells.
Describe the mechanism of action of β-lactamase inhibitors
β-lactamase inhibitors irreversibly bind to and inhibit the activity of β-lactamase enzymes, preventing them from hydrolyzing β-lactam antibiotics.
β-lactamase inhibitors can bind to a wide range of β-lactamase enzymes, including those produced by gram-negative and gram-positive bacteria.
By inhibiting β-lactamase enzymes, β-lactamase inhibitors prevent the degradation of β-lactam antibiotics, allowing them to exert their antibacterial activity and effectively target bacterial infections.
β-lactamase inhibitors are typically administered in combination with β-lactam antibiotics, such as amoxicillin-clavulanate, piperacillin-tazobactam, and ticarcillin-clavulanate, to enhance their antibacterial activity and broaden their spectrum of activity.
The combination of a β-lactam antibiotic and a β-lactamase inhibitor is often referred to as a β-lactam/β-lactamase inhibitor combination or a β-lactamase inhibitor-containing antibiotic.
Describe the rationale for the design of prodrugs of β-lactam antibiotics
Improved oral bioavailability: Many β-lactam antibiotics have poor oral bioavailability due to their low stability in acidic environments, poor membrane permeability, and susceptibility to degradation by gastrointestinal enzymes. Prodrugs can be designed to improve oral bioavailability by increasing stability and membrane permeability, and by reducing susceptibility to degradation.
Reduced toxicity: β-lactam antibiotics can cause adverse effects, such as allergic reactions, gastrointestinal disturbances, and neurotoxicity. Prodrugs can be designed to reduce toxicity by targeting the drug to specific tissues or by reducing systemic exposure to the active drug.
Targeted drug delivery: Prodrugs can be designed to target specific bacterial infections or tissues by using selective activation mechanisms, such as enzymatic activation by bacterial enzymes or pH-dependent activation.
Enhanced spectrum of activity: Prodrugs can be designed to improve the spectrum of activity of β-lactam antibiotics by increasing their stability and effectiveness against resistant bacterial strains.
Improved patient compliance: Prodrugs can be designed to reduce the frequency of dosing by increasing the duration of action of the drug, reducing the number of pills that need to be taken, and improving taste and palatability.
Relate the structure and physical properties of antibacterial drugs to their pharmacological activity
Mechanism of action: The mechanism of action of an antibacterial drug is determined by its chemical structure and functional groups. For example, β-lactam antibiotics have a β-lactam ring that inhibits bacterial cell wall synthesis, while fluoroquinolones have a fluorine atom that inhibits bacterial DNA synthesis. The chemical structure of the drug also determines its selectivity and specificity for bacterial targets, which can affect its pharmacological activity.
Spectrum of activity: The spectrum of activity of an antibacterial drug is determined by its mechanism of action and chemical structure. For example, some antibiotics are broad-spectrum and effective against a wide range of bacteria, while others are narrow-spectrum and only effective against specific bacterial species. The chemical structure of the drug can also affect its resistance to bacterial enzymes and its ability to penetrate bacterial cell walls.
Pharmacokinetic properties: The pharmacokinetic properties of an antibacterial drug are influenced by its physical properties, such as solubility, stability, and bioavailability. For example, some antibiotics have poor oral bioavailability due to low solubility or susceptibility to degradation in acidic environments. The physical properties of the drug can also affect its distribution and elimination from the body, which can impact its efficacy and toxicity.
Drug resistance: The structure of an antibacterial drug can also influence its potential for drug resistance. Some drugs are more prone to resistance due to their mechanism of action, while others are less prone due to their chemical structure. Additionally, the physical properties of the drug can affect its ability to penetrate bacterial cell walls and avoid drug efflux mechanisms, which can contribute to drug resistance.
Relate the structure and physical properties of antibacterial drugs to their pharmacological activity
Mechanism of action: The mechanism of action of an antibacterial drug is determined by its chemical structure and functional groups. For example, β-lactam antibiotics have a β-lactam ring that inhibits bacterial cell wall synthesis, while fluoroquinolones have a fluorine atom that inhibits bacterial DNA synthesis. The chemical structure of the drug also determines its selectivity and specificity for bacterial targets, which can affect its pharmacological activity.
Spectrum of activity: The spectrum of activity of an antibacterial drug is determined by its mechanism of action and chemical structure. For example, some antibiotics are broad-spectrum and effective against a wide range of bacteria, while others are narrow-spectrum and only effective against specific bacterial species. The chemical structure of the drug can also affect its resistance to bacterial enzymes and its ability to penetrate bacterial cell walls.
Pharmacokinetic properties: The pharmacokinetic properties of an antibacterial drug are influenced by its physical properties, such as solubility, stability, and bioavailability. For example, some antibiotics have poor oral bioavailability due to low solubility or susceptibility to degradation in acidic environments. The physical properties of the drug can also affect its distribution and elimination from the body, which can impact its efficacy and toxicity.
Drug resistance: The structure of an antibacterial drug can also influence its potential for drug resistance. Some drugs are more prone to resistance due to their mechanism of action, while others are less prone due to their chemical structure. Additionally, the physical properties of the drug can affect its ability to penetrate bacterial cell walls and avoid drug efflux mechanisms, which can contribute to drug resistance.
Describe the mechanism of action of glycopeptide antibiotics
Glycopeptide antibiotics, such as vancomycin, work by inhibiting bacterial cell wall synthesis. The bacterial cell wall is a critical structure that provides structural support and protection to the cell. It is composed of peptidoglycan, a complex polymer consisting of long chains of sugars and amino acids.
Glycopeptide antibiotics like vancomycin bind to the D-alanyl-D-alanine (D-ala-D-ala) terminus of the growing peptidoglycan chain, which is a critical component of bacterial cell walls. This binding prevents the transpeptidation reaction, which is necessary for cross-linking of the peptidoglycan chains and the formation of a stable cell wall. As a result, the bacterial cell wall becomes weakened and susceptible to lysis, leading to cell death.
Glycopeptide antibiotics have a unique mechanism of action compared to other antibiotics like beta-lactams. Beta-lactams work by inhibiting the activity of enzymes called penicillin-binding proteins (PBPs), which are involved in the cross-linking of peptidoglycan chains. However, some bacteria have evolved resistance to beta-lactams by producing beta-lactamase enzymes that can cleave the beta-lactam ring of these antibiotics, rendering them inactive.
Glycopeptide antibiotics, on the other hand, are not affected by beta-lactamase enzymes and are often used as a last resort for the treatment of serious bacterial infections that are resistant to other antibiotics.
Explain vancomycin resistance
Alteration of the cell wall target site: Bacteria can alter the D-alanine-D-alanine (D-ala-D-ala) target site on the cell wall, preventing vancomycin from binding effectively. This reduces the drug’s ability to inhibit cell wall synthesis and leads to resistance.
Production of enzymes that inactivate vancomycin: Some bacteria can produce enzymes, such as vancomycinases, that break down vancomycin and render it inactive.
Reduced uptake of vancomycin: Some bacteria have reduced permeability to vancomycin, which means that the drug cannot enter the cell and inhibit cell wall synthesis effectively.
Increased efflux of vancomycin: Some bacteria have developed efflux pumps that can pump out vancomycin from the bacterial cell, reducing the drug’s concentration and effectiveness.
