31 - Antibiotics & Anti-Fungals Flashcards
What proportion of bacteria are pathogenic?
Around 1/3 of bacteria are pathogenic
What phylogenetic domain do bacteria occupy?
They have their own phylogenetic domain
Outline the structure of bacteria
Single-cell microorganisms
Cell wall
Cell membrane
What is an important structural feature of gram positive bacteria and give an example?
Prominent peptidoglycan cell wall
e.g. staphylococcus aureus
What is an important structural feature of gram negative bacteria and give an example?
Outer membrane with lipopolysaccharide
Less prominent cell wall than gram positive
Don’t stain with gram stain
e.g. escherichia coli
What is an important structural feature of mycolic bacteria and give an example?
outer mycolic acid layer
(closer to gram positive than gram negative)
e.g. mycobacterium tuberculosis
Outline the stages of prokaryotic protein synthesis
1. Nucleic Acid Synthesis
Dihydropteroate (DHOp)
- Produced from paraaminobenzoate (PABA)
- Converted into dihydrofolate (DHF)
- DHOp enzyme
Tetrahydrofolate (THF)
- Produced from DHF by DHF reductase
- THF is important in DNA synthesis
- DHF reductase enzyme
2. DNA Replication
DNA gyrase (Topoisomerase)
Topoisomerase leads to released tension
Allows enzymes to get access to nucleic acids/enzymes
3. RNA Synthesis
RNA polymerase
- Produces RNA from DNA template
- Differ from eukaryotic RNA polymerase
4. Protein Synthesis
Ribosomes
- Produce protein from RNA templates
- Differ from eukaryotic ribosomes
Outline the different protein synthesis inhibitors that are used against bacteria as antibiotics
1. Nucleic Acid Synthesis
Dihydropteroate (DHOp)
- Sulphonamides inhibit DHOp synthase
- DNA can’t be made and so the bacteria dies
Tetrahydrofolate (THF)
- Trimethoprim inhibits DHF reductase
2. DNA Replication
DNA gyrase
- Fluoroquinolones (e.g. Ciprofloxacin) inhibit DNA gyrase & topoisomerase IV
- Prevent bacterial DNA from unwinding so bacteria can’t replicate
3. RNA Synthesis
RNA polymerase
- The rifamycins (e.g. Rifampicin) inhibits bacterial RNA polymerase
4. Protein Synthesis
Ribosomes
Most targeted area by intracellular antibiotics
Inhibited by:
- Aminoglycosides (e.g. Gentamicin)
- Chloramphenicol
- Macrolides (e.g. Erythromycin)
- Tetracyclines
THESE STAGES ARE THE 4 MAJOR INTRACELLILAR TARGETS OF ANTIBIOTICS
Outline the stages of bacterial wall synthesis
1. Peptidoglycan (PtG) Synthesis
A pentapeptide is created on N-acetyl muramicacid (NAM)
N-acetyl glucosamine (NAG) associates with NAM forming PtG
2. PtG Transportation
PtG is transported into periplasma across the membrane by a protein called bactoprenol
3. PtG Incorporation
PtG is incorporated into the cell wall when transpeptidase enzyme cross-links PtG pentapeptides
Outline the different antibiotics that target stages of bacterial wall synthesis (bacterial wall inhibitors)
1. PtG Synthesis
Glycopeptides (e.g. Vancomycin) bind to the pentapeptide preventing PtG synthesis
2. PtG Transportation
Bacitracin inhibits bactoprenol regeneration preventing PtG transportation
3. PtG Incorporation
β-lactams bind covalently to transpeptidase inhibiting PtG incorporation into cell wall
β-lactams include:
- Carbapenems
- Cephalosporins
- Penicillins
4. Cell Wall Stability
Becoming more important due to antibiotic resistance becoming more prevalent
Lipopeptide
- e.g. daptomycin
- disrupt Gram +ve cell walls
Polymyxins
- binds to LPS (lipopolysaccharides)
- disrupts Gram -ve cell membranes
Describe the timeline of antibiotic resistance
Antibiotics with new mechanisms are not being produced regularly
What are the different causes of antibiotic resistance?
CAUSES OF ANTIBIOTIC RESISTANCE
Unnecessary Prescription
Approx. 50% of antibiotic prescriptions not required
Livestock Farming
Approx. 30% of UK antibiotic use in livestock farming
Lack of Regulation
OTC availability in Russia, China, India
Lack of Development
Very few antibiotics in recent years
What percentage of bacteria have developed resistance?
About 70% of bacteria have developed resistance
What is the yearly death rate due to bacterial infection?
25,000 yearly death rate in Europe and US
List the difference resistance mechanisms of bacteria
Production of Destruction Enzymes
Additional Target
Alterations in Target Enzymes
Hyperproduction
Alterations in Drug Permeation
How does production of destruction enzymes lead to antibiotic resistance?
PRODUCTION OF DESTRUCTION ENZYMES
β-lactamases hydrolyse C-N bond of the β-lactam ring
Examples:
- Penicillins G & V
- gram positive
- Flucloxacillin & Temocillin
- β-lactamase resistant
- not affected by this enzyme produced by many bacteria
- Amoxicillin
- broad spectrum
- gram positive activity
- co-administered with clavulanic acid
How can an additional target lead to 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
How can hyperproduction lead to antibiotic resistance?
HYPERPRODUCTION
Bacteria significantly increase levels of DHF reductase
Not the most effective method of antibiotic resistance
Example:
E. coli produce additional DHF reductase enzymes making trimethoprim less effective
What are the two most common categories of anti-fungal drugs?
AZOLES - Fluconazole
POLYENES - Amphotericin
