Antibiotics and Anti-fungals Flashcards
Describe the membrane properties of the gram -ve and +ve bacteria
Gram Positive Bacteria
- Prominent peptidoglycan cell wall
E.g. Staphylococcus Aureus
Gram Negative Bacteria
- Outer membrane with lipopolysaccharide
E.g. Escherichia Coli
Mycolic Bacteria (pretty much gram +ve)
- Outer mycolic acid layer
E.g. Mycobacterium Tuberculosis
Describe the process of prokaryotic protein synthesis
1. Nucleic Acid Synthesis Dihydropteroate (DHOp) - Produced from paraaminobenzoate (PABA) - Converted into dihydrofolate (DHF) Tetrahydrofolate (THF) - Produced from DHF by DHF reductase - THF --> Important in DNA synthesis
- DNA replication
DNA gyrase
- Topoisomerase –> releases tension (unwinds the DNA) - RNA synthesis
RNA polymerase
- Produces RNA from DNA template
- Differ from eukaryotic RNA polymerase - Protein synthesis
Ribosomes (40s and 60s vs 30s and 50s)
- Produce protein from RNA templates
- Differ from eukaryotic ribosomes
List the protein synthesis inhibitors and which protein synthesis mechanism it inhibits?
1. Nucleic Acid Synthesis Dihydropteroate (DHOp) - Sulphonamides inhibit DHOp synthase Tetrahydrofolate (THF) - Trimethoprim inhibits DHF reductase
- DNA replication
DNA gyrase
- Fluoroquinolones (e.g. Ciprofloxacin) inhibit DNA gyrase & topoisomerase IV - RNA synthesis
RNA polymerase
- The rifamycins (e.g. Rifampicin) inhibits bacterial RNA polymerase
4. Protein synthesis Ribosomes Inhibited by: - Aminoglycosides (e.g. Gentamicin) - Chloramphenicol - Macrolides (e.g. Erythromycin) - Tetracyclines
How is the bacterial cell wall synthesised?
- Peptidoglycan (PtG) synthesis (occurs within the cytoplasm)
- A pentapeptide is created on N-acetyl muramic acid (NAM)
- N-acetyl glucosamine (NAG) associates with NAM forming PtG - PtG transportation
- PtG is transported across the membrane by bactoprenol into the periplasm - PtG incorporation
- PtG is incorporated into the cell wall when transpeptidase enzyme cross-links PtG pentapeptides
List the bacterial wall inhibitors and which mechanism it inhibits?
- PtG synthesis
- Glycopeptides (e.g. Vancomycin) bind to the pentapeptide preventing PtG synthesis - PtG transportation
- Bacitracin inhibits bactoprenol regeneration preventing PtG transportation - PtG incorporation
- beta-lactams bind covalently to transpeptidase inhibiting PtG incorporation into cell wall
- beta-lactams include:
1) Carbapenems
2) Cephalosporins
3) Penicillins - Cell wall stability
- Lipopeptide - (e.g. daptomycin) disrupt Gram +ve cell membranes
- Polymyxins - binds to LPS and disrupts Gram -ve cell membranes
List the 5 mechanisms which cause antibiotic resistance
Destruction enzymes
- Production of beta-lactamase
Additional target
- Different DHF reductase enzyme produced
Enzyme alteration
- Mutations in DNA gyrase enzyme
Hyperproduction
- Over-production of DHF reductase
Drug Permeation
- decrease drug influx, increase efflux systems
Describe mechanism 1 of antibiotic resistance
Production of destruction enzymes
beta-lactamases hydrolyse C-N bond of the beta-lactam ring
Examples of beta-lactamases
- Penicillins G and V –> Gram +ve (destroyed by beta-lactamases)
- Flucloxacillin and Temocillin –> beta-lactamase resistant
- Amoxicillin –> Broad spectrum
1) Gram -ve activity
2) Co-administered with Clavulanic acid otherwise destroyed by beta-lactamases.
Describe mechanism 2 of antibiotic resistance
Additional target
- Bacteria produce another target that is unaffected by the drug
Example
- E Coli produce different DHF reductase enzyme making them resistant to trimethoprim
Describe mechanism 3 of antibiotic resistance
Alterations in target enzymes
- Alteration to the enzyme targeted by the drug. Enzyme still effective but drug now ineffective
Example
- S Aureus - Mutations in the ParC region of topoisomerase IV confers resistance to quinolones
Describe mechanism 4 of antibiotic resistance
Hyperproduction
- Bacteria significantly increase levels of DHF reductase. The drugs work but there not able to remove all the reductase enzymes
Example
- E Coli produce additional DHF reductase enzymes making trimethoprim less effective
Describe mechanism 5 of antibiotic resistance
Alterations in drug permeation
- Reductions in aquaporins and increased efflux systems
- Together they reduce the drugs being able to get into the cell.
Examples
Primarily of importance in gram –ve bacteria
Describe the two main classes of anti-fungals
Azoles
- Inhibit cytochrome P450-dependent enzymes involved in membrane sterol synthesis. Prevents conversion of lanosterol to ergosterol
- Fluconazole (oral) –> candidiasis and systemic infections
Polyenes
- Interact with cell membrane sterols forming membrane channels. (punches holes in the cell wall - making it permeable)
- Amphotericin (I-V) –> systemic infections
