Dr. Timmins Flashcards
Potential targets for Viruses
- Simple genomes (bad)
- Very different from humans (good selectivity)
How do we treat viruses
- Host directed immune therapies
- Antiviral drugs
What are the downsides of antivirals
- Very few targets available
- Resistance can develop easily
- No “broad spectrum” antivirals available
What are the steps of a HIV life cycle
1) HIV fuses to host surface
2) HIV enters host cell
3) Viral DNA is formed by reverse transcriptase
4) Viral DNA fuses with host DNA
5) New Viral RNA is made
6/7) Viral RNA matures, leaves the host cell and is ready to infect new cells
Why do viruses NOT have efflux pumps?
-No electron transport chain
Bacterial Targets
- Mostly very different from us (Good selectivity)
- Bigger genomes= more targets (good)
- A lot of resistance (bad)
Mycobacterial resistance good/ bad news
- good = no plasmids to mediate resistance transfer
- bad = has a lot of resistance intrinsically
Fungal Targets
- Very similar to humans (Bad)
- Big genomes, but too similar to humans (Bad)
- Resistance mechanism to most agents (Bad)
- Most immunocompetent people are safe (good)
Fungal resistance to Echinocandins
-Mutations in FKS genes
Fungal resistance to Azoles
-Cyp51A gene inhibits drug binding
What led to a rapid increase in antifungal drugs in the 80s?
- The AIDS epidemic
- People were immunocompromised and getting sick all over the place!
Polyene MoA
- Insert themselves into the plasma membrane of fungi
- High affinity for ergosterol
- Cell becomes “leaky” and ions spill out
- The inside of the tunnel is polar (allowing for ions to flow through it)
What drives the selectivity and specificity of polyenes
- The number of double bonds and pi-pi stacking
- More double bonds = greater affinity for ergosterol
What are the benefits of using lipid AmB over the deoxycholate form?
- Less hepatotoxicity
- Less infusion reactions
- More stable
Which Lipid AmB looks like the death star
-L AmB (Ambisome)
Can you use AmB with an in-line filter
-No you dingus, AmB is too big to be able to pass though the in-line filter pores!
What is the MoA of Azoles
-Inhibits ergosterol synthesis by inhibiting 14 alpha demethylation
How does 14 alpha demethylation occur
- By 3 succesive aliphatic hydroxylations
- Followed by the elimination of formate and water
What are the three components of an azole and their roles
- Imidazole/Triazole warhead (binds to P450 heme site-to inhibit)
- Large hydrophobic R group (mimics lanosterol molecule- for targeting)
- Terminal polar group (helps with solubility)
Which type of azole is more specific
- Triazoles are more specific than imidazoles
- More nitrogens, more specific
Does Vfend (Voriconazole) work better in acidic or basic conditions
-Acidic!
Which Azole has the best nail penetration?
-Jublia (efinaconazole)
Why does Isavuconazole have great oral activity even though it has a quarternary ammonium?
- The positive charge is delocalized
- This allows for 98% oral absorption
How can fungi develop resistance to azoles?
- Mutations in the 14 alpha demethylase gene (decreasing azole affinity)
- Increased efflux pump activity
- Mutations in other genes
MoA of Terbinafine
- Inhibit squalene oxidase
- Can be used orally or topically
Echinocandins MoA
- Inhibit beta glucan synthesis (involved in cell wall formation)
- Does not obey the rule of 5s
How does resistance occur for echinocandins?
- Mutations in the FKS genes
- Upregulation of chitin
MoA of 5-flucytosine
- Prodrug
- Converted to 5-FU
- FUTP = inhibits protein synthesis
- FdUMP = inhibits DNA synthesis
Characteristics of the outer granuloma
- Oxic
- Neutral pH
- Active bacilli
- Oxidative phosphorylation
Characteristics of the necrotic core of granuloma
- Anoxic
- Acidic pH
- Dormant bacilli
- Glycolysis
Rifampicin MoA and characteristics
- Inhibits DNA dependent RNA polymerase
- Bactericidal
- Good oral bioavailability
- Ionizable amine drive solubility
How does resistance occur in Rifampicin
-Point mutations in rpoB decreases binding and inhibition
Where does Rifampicin work?
-Both in the outer and inner core of the granuloma
Pros and cons of Rifabutin
- Helpful when treating HIV/TB patients
- More side effects
- Neutropenia
- Uveitis arthritis
MoA of isoniazid (INH)
- first TB drug
- prodrug (activated by KatG)
- great oral availability
- Inhibits mycolic acid synthesis
Where does INH work?
- Outer granuloma only
- Needs O2 to be activated
How does resistance to INH occur
- Stop codon at KatG gene
- Amino acid change at active site
- Make more target protein, inhA (Can over come with high dose)
Pyrazinamide (PZA) MoA
- Prodrug activated by pncA
- More active in more acidic environment (more protonated)
- Has multiple targets
Where does PZA work?
- Only in the necrotic core
- Works better in lower pH found in granuloma core
How do mutations occur towards PZA
-Mutation in pcnA (prodrug)
Ethambutol (EMB) MoA
- Good bioavailability
- Targets cell wall arabinose transferase
- Helps increase efficacy of rifampin
- Low plasma levels because it is in the Granuloma!
Where does EMB work?
- Both in the outer granuloma and the core
- Works better in outer granuloma
Which anti-TB drugs work in the outer granuloma
- Rifampin
- Isoniazid
- Ethambutol (0.5)
Which anti-TB drugs work best in the necrotic core (caseum)
- Rifampin
- Pyrazinamide
- Ethambutol (0.25)
Which anti-TB drugs are prodrugs?
- Isoniazid
- Pyrazinamide
Ethionamide, prothionamide
- Major activity
- Prodrug
- Can be used to treat MDR/TB
Bedaquiline
- Inhibits mycobacterial ATP synthesis
- Bactericidal
- T1/2 = 5.5 months
