30. Antibiotics and anti-fungals Flashcards
Briefly compare gram positive, gram negative and mycolic bacteria
- G+ - thick peptidoglycan cell wall
- G- - thin peptidoglycan cell wall between inner membrane and outer lipopolysaccharide membrane
- Mycolic bacteria - like G+, with outer mycolic acid layer
Describe the production of tetrahydrofolate (THF) in prokaryotic nucleic acid synthesis?
Paraaminobenzoate (PABA) => dihydropteroate (DHOp) [DHOp synthase]
=> dihydrofolate (DHF) => tetrahydrofolate (THF) [DHF reductase]
What enzyme releases tension from the prokaryotic DNA to allow DNA replication?
DNA gyrase
Which enzyme produces RNA from prokaryotic DNA template?
RNA polymerase (different from eukaryotic RNA polymerase)
How do Sulphonamides affect bacteria?
- Inhibit DHOp synthase
- Prevent DHOp production
(most bacteria are resistant)
How does Trimethoprim affect bacteria?
- Inhibits DHF reductase
* Prevents THF production
How do Fluoroquinolones affect bacteria?
- Inhibit DNA gyrase + topoisomerase IV
* Prevent unwinding of DNA so it can’t be replicated
How do Rifamycins affect bacteria?
- Inhibit bacterial RNA polymerase
- Reduce subsequent production of proteins required for cell survival
(useful in mycobacterium)
Which antibiotics inhibit bacterial ribosomes (preventing protein production)
- Aminoglycosides
- Chloramphenicol
- Macrolides
- Tetracyclines
Is it generally harder to target G+ or G- bacteria?
G+ as they have a more prominent cell wall
How is the peptidoglycan wall synthesised?
- Pentapeptide created on N-acetyl muramic acid (NAM)
- N-acetyl glucosamine (NAG) and a pentapeptide associates with NAM, forming peptidoglycan
- This is transported from inside the cell to the periplasm (across the cell membrane) by a bactoprenol molecule
- It is incorporated into the cell wall
- Transpeptidase cross-links the pentapeptides
Which antibiotics interfere with the bacterial cell wall and cell membrane?
- Glycopeptides
- Bactitracin
- Beta-lactams
- Lipopeptides
- Polymyxins
How do glycopeptides e.g. vancomycin, inhibit the bacterial cell wall?
Bind the pentapeptide, preventing synthesis
How does bacitracin inhibit the bacterial cell wall?
Inhibits bactoprenol regeneration, preventing transportation
How do beta-lactams inhibit the bacterial cell wall
- Bind covalently to transpeptidase
- This inhibits peptidyglycan incorporation into a cell wall
(carbapenems, cephalosporins, penicillins)
Why are antibiotics targeting cell membranes used more?
Due to antibiotic resistance
What do lipopeptides and polymyxins do to bacteria?
- Lipopeptides - disrupt gram-positive cell membranes
* Polymyxins - bind to LPS and disrupt gram-negative cell membranes
What percentage of bacteria have developed resistance?
Around 70%
What are the causes of antibiotic resistance?
- Unnecessary and inappropriate prescription (50% not required)
- Livestock farming
- Lack of regulation (OTC in Russia etc.)
- Lack of development (few new antibiotics)
What resistance is there to beta-lactams?
- Beta-lactamase
- Hydrolyses the C-N bond of the beta-lactam ring of the antibiotics
• Can also have molecules around the beta-lactam ring, shielding it
- steric hindrance
Is penicillin G (IV) and V (oral) more effective for G+ or G-?
G+
Which penicillins are beta-lactamase resistant?
Flucloxacillin and temocillin
Is Amoxicillin beta-lactamase resistant?
Broad-spectrum, but not resistant
Co-administered with clavulanic acid (confers beta-lactamase resistance)
How can E. coli become resistant to trimethoprim?
- Produces different DHF reductase enzyme, a version not affected by the antibiotic
- Can produce more of the enzyme too for better evasion
How doe S. Aureus become resistant to quinolones?
Mutations in the ParC region of topoisomerase IV
How can bacteria become resistant through alterations in drug permeation?
- Reductions in aquaporins (antibiotics enter using these)
- Increased efflux systems
(Used in gram negative bacteria)
What are the 5 bacterial resistance mechanisms?
- Beta lactamase
- Production of additional targets (e.g. different version of an enzyme produced that is unaffected by AB)
- Alteration in the target enzyme (same enzyme)
- Hyper-production
- Alteration in drug permeation
What does the fungal cell membrane contain that is a common drug target?
Ergosterol
What are the 4 different types of fungal infections?
1) Superficial
2) Dermatophyte (skin, hair or nails)
3) Subcutaneous
4) Systemic (primarily respiratory tract)
What are the 2 most common categories of anti-fungals?
Azoles e.g. fluconazole
Polyenes e.g. amphotericin
How do Azoles work?
Inhibit ergosterol production
• Inhibit CYP450-dependent enzymes involved in membrane sterol synthesis
• Important in ergosterol production, which is incorporated into the cell wall
What is fluconazole (oral) used for?
Candidiasis and systemic infections
How do polyenes (amphotericin) work?
- Create pores in the cell membranes of fungal cells
- Binds to ergosterol
- Cell becomes permeable and bursts
(makes pores in all cells, so there are bad side effects)
What is amphotericin (I-V) used to treat?
Systemic infections
