Antibiotics and antifungals Flashcards
Bacteria
- single cell microorganisms (cell wall and cell membrane included)
- entire phylogenetic domain
- ~ one third are pathogenic
Gram positive bacteria membrane properties
- prominent thick peptidoglycan cell wall
- EG: Staphylococcus Aureus
Gram negative bacteria membrane properties
- outer membrane with lipopolysaccharide
- EG: Escherichia Coli
Mycolic bacteria membrane properties
- outer mycolic acid layer
- EG: Mycobacterium Tuberculosis
Prokaryotic protein synthesis
1) Nucleic Acid synthesis
2) DNA replication
3) RNA synthesis
4) Protein synthesis
Nucleic acid synthesis
1) Dihydropteroate (DHOp)
- produced from paraaminobenzoate (PABA)
- converted into dihydrofolate (DHF)
- sulphonamides inhibit DHOp synthase
2) Tetrahydrofolate (THF)
- produced from DHF by DHF reductase
- important in DNA synthesis
- Trimethoprim inhibits DHF reductase
DNA replication
1) DNA gyrase
- Toposimerase which releases tension in DNA
- Fluoroquinolones (eg: Ciprofloxacin) inhibits DNA gyrase and topoisomerase IV
RNA synthesis
1) RNA polymerase
- produces RNA from DNA template
- differs from eukaryotic RNA polymerase
- rifamycins (eg: Rifampicin) inhibits bacterial RNA polymerase
Protein synthesis
1) Ribosomes
- produces protein from RNA templates
- prokaryotic ribosomes (70S) differ from eukaryotic ribosomes (80S)
- ribosomes inhibited by aminoglycosides (eg: Gentamicin), chloramphenicol, macrolides (eg: erythromycin) and tetracylcines
Bacterial wall synthesis
1) Peptidoglycan synthesis
2) Peptidoglycan transportation
3) Peptidoglycan incorporation
Peptidoglycan synthesis
- pentapeptide is created on N-acetyl muramic acid (NAM)
- N-acetyl glucosamine (NAG) associates with NAM forming peptidoglycan
- Glycopeptides (eg: vancomycin) binds to pentapeptide to prevent peptidoglycan synthesis
Peptidoglycan transportation
- peptidoglycan transported across membrane by bactoprenol
- Bacitracin inhibits bactoprenol regeneration preventing peptidoglycan transportation
Peptidoglycan incorporation
- peptidoglycan incorporated into cell wall when transpeptidase enzyme cross-links peptidoglycan pentapeptides
- Beta-lactams bind covalently to transpeptidase to inhibit peptidoglycan incorporation into cell wall (eg: carbapenems, cephalosporins, penicillins etc)
Cell wall stability
- Lipopeptide (eg: Daptomycin) disrupts gram positive cell walls
- Polymyxins bind to lipopolysaccharides and disrupts gram negative cell membranes
Threat of antibiotic resistance
0~70% of bacteria developed resistance
-25,000 yearly death rate in Europe and the US
Causes of antibiotic resistance
- Unnecessary prescription (~50% of antibiotic prescriptions are not required)
- Livestock farming (~30% of UK antibiotic use in livestock farming)
- Lack of regulation (over the counter availability in Russia, China and India)
- Lack of development (very few antibiotics in recent years)
Production of destruction enzymes (resistance mechanism)
-Beta-lactamases hydrolyse C-N bond of the drug’s beta-lactam ring
Examples:
- Penicillins G and V=gram positive bacteria (beta-lactamase non-resistant)
- Flucloxacillin and Temocillin=beta-lactamase resistant
- Amoxicillin (broad spectrum antibiotic)=gram negative bacteria activity and often co-adminstered with Clavulanic acid
Additional targets (resistance mechanism)
-bacteria produce another target that is unaffected by drug (different DHF reductase enzyme)
Example:
-E. Coli produces a different DHF reductase enzyme to make them resistant to trimethoprim
Alteration in target enzymes (resistance mechanism)
- alteration/mutation to enzyme targeted by drug
- enzyme still effective but drug now ineffective
Example:
-Staphylococcus Aureus=mutations in ParC region of topoisomerase IV confers quinolone resistance
Hyperproduction (resistance mechanism)
-bacteria significantly increase DHF reductase levels (overproduction)
Example:
-E. Coli=produces additional DHF reductase enzymes making trimethoprim less effective
Alterations in drug permeation (resistance mechanism)
-reductions in aquaporins (decreased drug influx) and increased efflux systems
Example:
-important in gram negative bacteria
Fungal infection classification
- Classified in terms of tissue/organs
1) Superficial (outermost skin layers)
2) Dermatophyte (skin, hair or nails)
3) Subcutaneous (innermost skin layers)
4) Systemic (primarily respiratory tract)
Antifungals
-15 anti-fungal drugs licensed in UK
Two most common categories:
- Azoles
- Polyenes
Azoles
-inhibits cytochrome P450-dependent enzymes involved in membrane sterol synthesis (ergosterol synthesis)
Example:
-Fluconazole (oral admin)=treats candidiasis and systemic infections
Polyenes
-interacts with cell membrane sterols (ergosterols) forming membrane channels/pores
Example:
-Amphotericin (I.V. admin)=treats systemic infections
