Antifungal (MC) - Block 3 Flashcards
How are fungi similar to mammalian cells?
- Eukaryotic
- Biochemical structures and cell membranes
- DNA is organized into chromosomes in the cell nucleus containing distinct cytoplasmic organelles
- Share similar mechanisms for DNA replication and protein synthesis
What is the major sterol of fungi?
Ergosterol through 14-reductase
How does ergosterol differ from cholesterol?
Additional double bonds hive the structure flexible rigidity
What is the primary sterol in mammals?
Cholesterol
Disruption of protein/carb matrix in a defective cell wall leads to?
Cells become sensitive to osmotic lysis similar properties to antimicrobial cell wall inhibitors
What are the types of fungal infections?
- Superficial mycoses (Dermatophytoses)
- Deep seated mycoses (systemic mycoses)
Dermatophytoses activity?
Capable of digesting keratin of the skin
How do superficial mycoses differ from systemic?
Non-contagious unless immunocompromised and neonates
Why are glucan synthesis inhibitors safe?
No analogous mammalian cell wall structure (no harm to human cells)
What is the target for glucan synthesis inhibitors?
b1,3-glucan synthase
What are the types of echinocandins?
Fungicidal against yeast (Candida)
Fungistatic against mold (Aspergillus)
What are the therapeutic uses for echinocandins?
- Broad range (especially against all candida)
- Used in azole resistant candida
- Low toxicity
- Better than Amphotericin B and fluconazole against yeast infection
Where does echinocandin B derive from?
Precursor of Anidulafungin -> effective against A. nidulans
Types of echinocandins?
- Caspofungin
- Micafungin
- Anidulafungin
Indication of caspofungin?
- EMpiric
- Treatment of invasive aspergillosis and Candida
Indication of micafungin?
Treatment of candidemia and prophylaxis
How does lipophilicity contribute to echinocandin activity?
Long lipophillic tail: hemolytic in vitro (insertion into cell membrane)
Short lipophillic tail: loss of activity
LogP >3.5: antifungal
What enzymes are targeted by ergosterol synthesis drugs?
- Squalene epoxidase
- 14a-demethylase
- Δ14-reductase (not approved)
- Δ7, Δ8 isomerase (not approved)
What is ERG1?
Squalene metabolized by squalene epoxidase to squalene epoxide
What is ERG11?
Lanosterol’s C14 become dimethylated by C14-demethylase
What is ERG24?
d14-reducase reduces structure
What is ERG2?
C8-isomerase shifts 8-9 alkene
What is the SAR of squalene epoxidase inhibitors?
Allylamine
Activity of squalene epoxidase inhibitor?
Narrow spec and only effective against nail and skin dermatophytes
Are there selectivity issues of squalene epoxidase inhibitors?
Enzyme is present in mammalian cholesterol pathways, but have lower affinity for these agents and most are used topically
What is the major functional group for squalene epoxidase inhibitors?
Allyl amine
What are the types of squalene epoxidase inhibitors?
- Naftifine
- Terbinafine
- Butenafine
- Tolnaftate
Describe the activity of 14α-demethylase Inhibitors?
CYP450 enzyme that are present in mammalian cholesterol pathway
* High probability of CYP450 interactions
Describe the binding of 14α-demethylase Inhibitors?
Azole drug binds to Fe in place of histidine -> CYP can no longer bind/carry molecular O2 effectively inhibiting the enzymatic process
How are all CYP enzymes structurally similar?
Contains a heme cofactor coordinating molecular O2
Describe the activity of azoles based on its structure?
Chain mimics sterol scaffold
Azole bind to Fe
SAR of azole?
- 1,2, 4- triazole with pKa of 6.5-6.8 (charged at vaginal pH)
- N3 of imidazole and N4 of imidazole of triazole binds to P450 iron
- Most active ones have 2-3 aromatic rings, one can be substituted with halogens or nonpolar group (most have fluorine)
Target of azole
14a-demethylase
Types of azoles?
- Clotrimazole
- Butoconazole
- Econazole
- Miconazole
- Ketoconazole
- Itraconazole
- Posaconazole
- Fluconazole
- Voriconazole
DDI of ketoconazole?
Potent CYP3A4 inhibitor
What isavuconazonium sulfate?
Systemic prodrug formulation (enhanced solubility) used for the tx of aspergillosis and candidiasis
Examples of Δ14 reductase inhibitor? Indication?
Amorolfine: treatment of dermatophytosis
Examples of Δ7, Δ8-Isomerase Inhibitors
Amorolfine
What are the groups of polyene membrane disrupters?
A 26-member ring: Natamycin
A 38-member ring: Amphotericin B and Nystatin
Polyene MOA?
Binds to ergosterol -> formation of pores:
* Increase permeability to proteins and monovalent and divalent cations
* Eventual cell death
Attach with higher affinity to ergosterol over cholesterol membranes
Describe the toxicity of polyene specifically amphotericin B?
Amphotericin B: may induce oxidative damage in fungal cells
* At higher concentrations, amphotericin B binds to cholesterol in mammalian cell membranes
* Nephrotoxicity
Describe the binding of amphotericin B? SAR?
H-bond between hydroxyl, carbonyl, and amino groups of the drug and membrane making the channel stable:
Inidication for amphotericin B?
Lethal fungal infections such as coccidimycosis and histoplasmosis:
* Systemic infection
* Admin intrthecally to get into the CNS
How does nystatin compare to amphotericin?
- 38 membered ring
- No systemic absorption
- Toxic when given IV
- MOA is same as amphotericin
Indication for nystatin?
Dermal and GI infections from Candida albicans
What is natamycin?
26-membered macrolactone, MOA is similar to amphotericin B
* Topical as cream, eyedrop, lozenge
* No systemic absorptio
What polyene is given IV?
Amphotericin B
What are DNA and protein syntheis difficult targets for selective toxicity?
Fungal cells share similar homology in DNA replication and RNA translation with mammalian cells
What enzyme is responsible for flucytosine transport?
Cystosine permease that converts drug to 5-fluorouracil (5-FU) in the cytoplasm
That is the toxic form of flucytosine?
5-FdUMP that traps thymidylate synthase and folate
MOA of flucytosine?
5-FU is phosphorylated and incorporated into RNA -> miscoding and halts protein syntheis
* Inhibits DNA synthesis through thymidylate synthetase
MOA of griseofulvin?
Inhibits fungal cell mitosis by disrupting mitotic spindle formation (critical for cellular division)
Indiation for griseofulvin?
Dermatophytes:
* Enters in the structure of the precursors of keratin
* Doesn’t have local activity (not topical)
Fatty acid product that is a natural antifungal?
Sebum
