Antibiotics and antifungals Flashcards
General info about background
Single-cell microorganisms - cell wall & cell membrane
An entire phylogenetic domain
~ 1/3 are pathogenic
Differentiate gram +ve and gram -ve bacteria
Give an important example of each
Gram Positive Bacteria
Prominent peptidoglycan cell wall
E.g. Staphylococcus Aureus
Gram Negative Bacteria
Outer membrane with lipopolysaccharide
E.g. Escherichia Coli
What is mycolic bacteria
Outer mycolic acid layer
E.g. Mycobacterium Tuberculosis
(kind of seen as gram +ve)
Outline nucleic acid synthesis in prokaryotes
Dihydropteroate (DHOp)
- Produced from paraaminobenzoate (PABA)
- Converted into dihydrofolate (DHF)
Tetrahydrofolate (THF)
- Produced from DHF by DHF reductase
- THF –> Important in DNA synthesis
Outline an important mechanisms in DNA replication
DNA gyrase
-Topoisomerase –> releases tension
Allows access of other enzymes
Outline important mechaisms in RNA synthesis
RNA polymerase
Produces RNA from DNA template
`Differ from eukaryotic RNA polymerase
Outline important mechasnism of the protein synthesis
Ribosomes
Produce protein from RNA templates
Differ from eukaryotic ribosomes
(30S and 50S)
How do sulphonamides work
Sulphonamides inhibit DHOp synthase (Dihydropteroate)
To reduce DNA synthesis
How do trimethoprim work
Trimethoprim inhibits DHF reductase
To reduce DNA….
Combination with sulphonamide used sometimes
How do quinolones/fluoroquinolone work
Give an example
Fluoroquinolones (e.g. Ciprofloxacin) inhibit DNA gyrase & topoisomerase IV
Cannot replicate DNA if the DNA is not unwound
How to rifamycins work
What is it used to treat
The rifamycins (e.g. Rifampicin) inhibits bacterial RNA polymerase
Prevents RNA and thus protein production, so the bacteria cannot produce elements needed to survive.
Drug interaction–> CYP450 enzyme inducer (along with carbamazepine)
Used to treat TB
Which drugs affect the ribosomes
Aminoglycosides (e.g. Gentamicin)
Chloramphenicol
Macrolides (e.g. Erythromycin)
Tetracyclines
Drug interactin of erythromycin
Erythromycin and related ABs are CYP450 INHIBITORS
So is ciprofloxacin (a flouroquinolone) and related ABs
as well as ketoconazole
and cimetidine (like ranitidine)
Outline peptidoglycan cell wall synthesis
A pentapeptide is created on N-acetyl muramic acid (NAM)
N-acetyl glucosamine (NAG) associates with NAM forming PtG
Happens within the cytplasm
Outline PtG transport
The peptidoglycan is produced within the cytoplasm, so needs to be transported through the membrane into the cell wall
PtG is transported across the membrane by bactoprenol
Outline PtG incorporation
Now the PtG has made it to the cell wall, it needs to be incoroporated
PtG is incorporated into the cell wall when transpeptidase enzyme cross-links PtG pentapeptides
Function of glycopeptide drugs
Give an example
Glycopeptides (e.g. Vancomycin) bind to the pentapeptide preventing PtG synthesis
Which drug targets PtG transportation
Bacitracin inhibits bactoprenol regeneration preventing PtG transportation
Which drugs target PtG incorporation
Give examples of PtG incorporation
b-lactams bind covalently to transpeptidase inhibiting PtG incorporation into cell wall
Carbapenems
Cephalosporins
Penicillins
Outline drugs affect cell wall stability and how they work. Give an example of each
THIS INVOLVES CHANGING THE MEMBRANE WHICH AFFECTS CELL WALL STABILITY
Lipopeptide - (e.g. daptomycin) disrupt Gram +ve cell WALL
Polymyxins - binds to LPS & disrupts Gram -ve cell MEMBRANE
Causes of antibiotic resistance
+ list the methods of AB resistance
Unnecessary prescription
(~ 50% of antibiotic prescriptions not required)
Livestock farming
(~ 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)
- Production of destruction enzymes
- Additional targets
- Alter the target site
- Hyperproduction
- Alterations in drug permeation
Outline production of destruction enzymes
b-lactamases hydrolyse C-N bond of the b-lactam ring
Give examples of ABs which are, and those which ARE NOT affected by beta-lactamases
What is amoxiclav
ARE: penicillin G and V
ARE NOT: Flucloxacillin & Temocillin are b-lactamase resistant (I.E. NOT AFFECTED BY BETA LACTAMASE)
Amoxicillin is Broad spectrum (which on it’s own is susceptible to beta lactamases)
- Gram -ve activity
- Co-administered with Clavulanic acid (this is a beta lactamase INHIBITOR, so stops the AB from being broken down)
Outline resistance due to additional target with example
Bacteria produce another target that is unaffected by the drug
E Coli produce different DHF reductase enzyme making them resistant to trimethoprim
Outline resistance due to alteration target enzymes with example
Alteration to the enzyme targeted by the drug. Enzyme still effective but drug now ineffective
S Aureus - Mutations in the ParC region of topoisomerase IV confers resistance to quinolones
Outline resistance due to hyperproduction with example
Bacteria significantly increase levels of DHF reductase
E Coli produce additional DHF reductase enzymes making trimethoprim less effective
Outline alterations in drug permeation as a resistance mechanism
Give examples
Reductions in aquaporins & increased efflux systems
Primarily of importance in gram –ve bacteria
Classify fungal infectins
Superficial - Outermost layers of skin
Dermatophyte - Skin, hair or nails
Subcutaneous - Innermost skin layers
Systemic - Primarily respiratory tract
2 types of antifungals
Azoles: Fluconazole
Polyenes: Amphotericin
Mechanism of azoles action
Give an example
Inhibit cytochrome P450-dependent enzymes involved in membrane sterol synthesis
Fluconazole (oral) candidiasis & systemic infections
(similar to vancomycin)
Mechanism of polyenes action
Give an example
Interact with cell membrane sterols forming membrane channels, to disrupt cell wall
Amphotericin (I-V) –> systemic infections
