MST 2 Flashcards
What is a NARROW spectrum?
- Specific drugs
- Targets gram + OR -
- Useful when drug agent is KNOWN
What is a BROAD spectrum?
- Targets BOTH gram + & -
- Useful when drug agent is UNKNOWN
Describe & list the mechanism of action of β-lactam antibacterial drugs
- β-lactam binds to active site of PBP
- Covalent bonds form between drug & serine residue in PBP
- Irreversibly inhibits PBP
- Interrupts cell-wall formation
- Cell is compromised to the extracellular matrix
- Bacteria cells dies/lysis
PBP= pencillin binding protein
How does β-lactam bind to the active site of PBP?
β-lactam mimics the D-Ala-D-Ala end of the transpeptide (PBP)
* binds to the pentaglycyl unit before the transpeptidase
How does β-lactam irreversibly inhibit PBP?
prevents the PBP from connecting the pentapeptide chains from one NAG to another (usually forms the cell wall)
What is PBP?
Penicillin-Binding Proteins = transpeptidase = enzyme that CROSS-LINKS peptidoglycan strands using D-Ala-D-Ala
What are the use of β-lactam antibacterial drugs?
for bacterial infection = causes the bacterial cell to die due to compromising the cell wall
* bacteria is hyperosmotic = contents rush in & kills it
DRUGS
* Penicillins (+)
* Cephalosporins (+/-)
* Carbamenpens (+/-)
(-) = two cell wall
Name the two bacterial antimicrobial resistance
Acquired Resistance & Innate Resistance
What is ACQUIRED resistance?
-
transfering/sharing of information (plasmid) to other bacteria
- used to share information of different resistance mechanisms
-
Vertical & Horizontal transfer of resistance genes
- Vertical = gene passed fown to daughter cells
- Horizontal = gene shared between bacteria thorugh transformation, transduction or conjugation
List and explain the 4 different INNATE resistance
1. Blocking entry
* Porin mutation = reduce uptake (-)
2. Inactivating enzymes
* Increased production of enzyme = inactivate drug (β-lactamase)
3. Efflux of Antibiotic
* Production of enzyme = increase efflux of drug (p-glycoprotein)
4. Alteration of target molecule
* Reduce affinity for target
What are the 4 targets for antiviral therapy in the virus life cycle? Explain/give an example
1. Entry = Cell Surface Receptors
* e.g. Fusion inhibitors
* block virus from binding & fusing to host cell membrane
2. Entry, Uncoating, Release
* E.g. Ion Channel blockers
* prevents uncoating & release of genetic material
3. Replication = RNA/DNA Replication, DNA nuclear transcription, RNA translation
* e.g. Polymerase inhibitors & Protease inhibitors
* stop replication
4. Release = prevent release to other cells
* e.g. Neuraminidase inhibitors
How does the overexpression of RTK reveal targeted therapeutic strategies? Use Imatinib as an example
- Overexpression of RTK = disrupts normal cellular signalling & promotes uncontrolled growth
Imatinib
* potent & selective inhibitor for ABL, PDGFR, KIT Tyrosine Kinase (cell surface receptor proteins)
* Imatinib significantly reduces kinases ability to bind ATP = potent inhibition of their signalling activity = cease cancer cell growth & survival
* selectively kills BCR-ABL expressing cells in vitro & in vivo
How does the oncogenic KRAS reveal targeted therapeutic strategies? Use Sotorasib as an example
- since KRAS usually regulates cell growth, differentiation & survival = mutation = always on
Sotorasib
* Small molecule inhibitor = covalently & irreversibly binds to KRAS G12C oncoprotein
* Interacts with cysteine residue (induced by mutation)
* occupies pocket beneath switch II region in inactive (GDP bound) conformation of KRAS G12C
* MECHANISM: Sotorasib = binds covalently to specific pocket in mutated KRAS protein = trap enzyme in INACTIVE state = prevents downstream effector (usually promotes uncontrolled cell growth)
Cysteine = only found in KRAS oncogenetic form = not affect wild type
In a Lollipop Plot, list how cancer gene, tumour supressor & oncogene is distinguished.
Cancer gene = highly mutated
Tumour supressor gene = mutation scatters with no clear hotspot
* high truncating percentage
Oncogene = mutation hotspot
* cluster of mutations concentration at particular spot in gene
truncating = creates shorter gene
In an oncoprint, state what Missense mutation, Truncating mutation & Alterations mean
ALSO = state how to detect potential tumour suppressor gene
- Missense mutation = amino acid changes
- Truncating mutation = protein shortening
- Alterations = amplifications or deletions of gene segments
Tumour suppressor gene
* high percentage of truncating mutation
What is airway remodelling and what is it affected by?
structure of airway wall changes = cell growth & breakdown is balanced
Affected by:
* growth factors e.g. PDGF, FGF, TGFβ, VEGF
* cytokines e.g. IL-5, GM-CSF
* chemokines e.g. RANTES, eotaxin, CXCL8
* lipid mediators e.g. PGE2
* extracellular matrix components e.g. collagen
What is the mechanism of airway CONTRACTION?
-
Increase in intracellular Ca2+ = triggered by signals, hormones, or inflammatory mediators
Enter cell = voltage gated Ca2+ channels OR released from internal stores = signals = phospholipase C & inositol triphosphate - Ca2+ binds to calmodulin = activates Myosin Light Chain Kinase (MLCK) enzyme
-
MLC phosphorylated = actomyosin ATPase activated (actual motor for contraction)
MLCK phosphorylates site on protein MLC -
Cell shortening = cross bridges between actin & myosin BREAK & REFORM = sliding past each other
Shortening of individual muscle cell = shortening of airway smooth muscle layer
What are the factors INCREASING Ca2+?
contraction
- Vca2+ channels
- Phospholipase C
- Inositol trisphosphate IP3
* Release from intracellular stores
What is the mechanism of airway RELAXATION?
1.Decrease influx of Ca2+ entering cell = closure of VCa2+ channels OR reduced release from internal stores
2.Increase Ca2+ Removal
- Plasma membrane Ca2+ ATPase = pump Ca2+ out of cell
- Sarcoplasmic reticulum Ca2+ ATPase(SERCA) = pump calcium back into internal stores
What are the factors DECREASING Ca2+?
relaxation
- Plasma Ca2+ ATPase (Efflux)
- Sarcoplasmic reticulum Ca2+ ATPase
- Uptake into internal stores
How is contractile proteins inhibited during airway relaxation?
Myosin Light Chain Phosphatase Activation
* MLCP enzyme = removes phosphate added by MLCK during contraction
* Dephosphorylation = deactivates actomyosin complex = prevent cross-bridge formation & actomyosin ATPase activity
What are the rationale for drug combinations in asthma?
targetting different aspects of asthma
- As asthma involves both inflammation & airway hyperresponsiveness = increased sensitivity to triggers
- inhaled steroids = target chronic inflammation in airways, reduce swelling & mucus production
- LABA = relax smooth muscle surrounding airways causing bronchodilation = provides quick relief from symptoms but dont address underlying inflammation
- COMBINE BOTH
What are the similar characteristics of symptoms between COPD & Asthma?
- Eosinophilic inflammation
- Recurrent exacerbation
What are the general similarities between Asthma and COPD?
- chronic inflammatory disorder
- obstructive lung disease
- airway obstruction
- difficulty breathing
