Mycology Flashcards
Which three commonly used classes of antifungal agents are there? (3)
- Azoles
- Echinocandins
- Amphotericin B
What is the downside of amphotericin B? What is its upside?
Downside: nephrotoxicity
Upside: very little resistance to this compound
What is the advantage of azoles? What is their disadvantage?
Advantage: less side effects than amphotericin B
Disadvantage: resistance develops quickly
What is microbial resistance (definition) in fungi?
Decreased susceptibility of a fungal strain to an antifungal agent in standardized in vitro susceptibility testing
What are possible causes for microbial resistance in fungi? (2)
- Intrinsic/natural resistance
- Acquired resistance
What is clinical resistance (in fungi)?
Therapeutic failure -> patient responds inadequately to antibacterial drug following administration of the standard dose
What are causes of clinical resistance in fungi? (4)
- Site of infection
- Presence of catheters
- Host immune status
- Host mutations (quick drug metabolism)
Why can the presence of cathethers cause clinical resistance to antifungal drugs?
Can induce formation of biofilms
How can fungi acquire resistance? (2)
- Due to treatment of patients
- Due to use of antifungal agents in the environment
To which drug class does amphotericin B belong?
Polyenes
What is the mechanism of action of amphotericin B/polyenes?
Disruption of the fungal cell membrane by formation of pores in the membrane, causing cellular contents to leak out
To which compound of the fungal cell membrane does amphotericin B bind?
Ergosterol
Amphotericin B is a [fungicidal/fungistatic] drug
Fungicidal
What is the advantage of the fungicidal nature of amphotericin B?
Makes it harder for fungi to become resistant -> no time to adapt
Which mechanisms can lead to resistance to amphotericin B? (3)
- Reduced amounts of ergosterol in cell membrane
- Alteration of fungal cell membrane -> ergosterol replaced, amphotericin B can no longer bind
- Alteration of fungal cell wall -> thicker cell wall blocks amphotericin B access to the membrane
What is the mechanism of action of azoles?
Interferes with the biosynthesis of ergosterol by blocking Erg11, causing the production of toxic Erg3
Which enzymes are inhibited by azoles?
Erg11/CYP51
Which drug works via the same pathway as azoles? To which class does it belong?
Terbinafine, belonging to the allylamines
Azoles are [fungicidal/fungistatic]
Fungistatic
What is the downside of the fungistatic nature of azoles?
Allows for development of resistance
Which three groups of azoles can be identified? What sets them apart?
- Imidazoles = 2 nitrogen atoms in their ring
- Triazoles = 3 nitrogen atoms in their ring
- Tetrazoles = 4 nitrogen atoms in their ring
Which drug belongs to the imidazoles?
Ketoconazole
Which drugs belong to the triazoles? (4)
- Fluconazole
- Voriconazole
- Itraconazole
- Posaconazole
Which drug belongs to the tetrazoles?
Otesconazole
What are the mechanisms of resistance to azoles? (5)
- Target changed -> reduced drug-target interaction
- Increased target copy number
- Reduction in intracellular drug concentration via efflux transporters and reduced uptake
- Modification of other ergosterol biosynthesis pathway elements
- Biofilms and persister cells
How do azoles enter bacterial cells?
Passive diffusion
How can target changes reduce azole susceptibility?
Enzyme is changed in such a way that it can still function in the pathway, but can no longer be affected by the drug
True or false: when a fungus develops resistance to one azole, it acquires resistance to all of them
False; fungi can become resistant to some azoles, while remaining susceptibility to others
How does increased target copy number reduce azole susceptibility?
Increased number of Erg11 enzymes -> amount of azoles no longer sufficient to suppress activity
Which two mechanisms can lead to increased target copy numbers, leading to azole susceptibility? By how much do they elevate Erg11?
- Mutation in promotor gene UPC2 -> gain of function leading to 6-7x fold increase of Erg11
- Aneuploidy of chromosome 5, leading to 1,5-fold increase of Erg11
Which two groups of drug-efflux transporter genes and proteins can be found in fungi?
- DCR-genes -> ABC-transporter
- MMDR-genes -> proton pump
How can overexpression of drug efflux transporters be induced, leading to azole resistance?
Overexpression of transcription factor TAC1 (aneuploidy or gain of function mutations)
Some candida species have both Erg11 and TAC1 on chromsome 5. What can be the effect of this?
Strong resistance to azoles in case of aneuploidy
Which two mechanisms of resistance to azoles are least common?
- Modification of other pathway elements
- Biofilms and persister cells
Which pathway elements (other than Erg11) can be modified that lead to azole resistance?
Erg3 inactivation -> prevents production of toxic sterols in case of Erg11 blocking by azoles
How do biofilms/persister cells lead to resistance to azoles? (2)
- Prevent penetration of antifungal agents to the fungus
- Biofilms often have a metabolically inactive core -> no mechanisms to inhibit
What is the mechanism of action of echinocandins?
Interference with fungal cell wall synthesis by inhibiting β-glucan synthesis
Which two components comprise the majority of fungal cell walls?
- β-glucan
- Chitin
Echinocandins are large molecules. What is the effect of this?
Slow diffusion into some fungal species
What are triterpenoids? What is their advantage?
New class of drugs that interferes with β-glucan syntehsis. Smaller molecules than echinocandins -> more easily diffuses through cell walls
True or false: resistance to echinocandins also leads to resistance to triterpenoids
False; due to their different structures, resistance to one class does not lead to resistance to the other
To which group of fungi are echinocandins fungistatic? And for which group are they fungicidal?
Fungistatic for Aspergillus spp.
Fungicidal for Candida spp.
What is the ‘paradoxical effect of echinocandins’? What causes this?
Concentrations slightly above MIC leads to killing, but even higher concentrations lead to decreased killing. Caused by adaption of fungi to echinocandins at higher concentrations
What does fungal adaptation to echinocandins lead to? (4)
- Activation of stress pathways
- Generation of cells which tolerate antifungal agents
- Accumulation of mutations
- Emergence of stable resistant isolates
How can fungi become tolerant to echinocandins?
Upregulation of chitin synthesis -> maintains cell wall integrity even when there is a lack of β-glucan
What are mechanisms of resistance to echinocandins? (3)
- Target modification, leading to reduced drug-target interaction
- Increased target copy number
- Biofilms and persister cells
