In this lecture we’re gonna cover the pharmacology of antifungal drugs
so let’s get right into it. The similarity of fungal and mammalian cells creates a
number of challenges for designing drugs that are selectively toxic to fungal cells
but not to our own cells. The only significant difference between fungal and mammalian cells
are the presence of fungal cell walls and a small structural difference in the plasma membrane.
Now, the cell wall of most fungi is composed of mannoproteins
and rigid layers of complex polysaccharides; β-1,3 and β-1,6-linked glucans as well as chitin.
Being external, the cell wall offers mechanical strength and acts as a barrier,
thus protecting the fungus from the hostile environment. Underneath this wall lies the
plasma membrane made up of phospholipid bilayer. The major sterol found in fungal plasma membranes
called ergosterol, acts to maintain membrane integrity in the same capacity as cholesterol,
which is the major sterol found in mammalian cell membranes. Lastly, the plasma membrane
also houses multisubunit enzymes that are responsible for fungal cell wall construction.
Now, because of its crucial functions and unique structural properties, ergosterol is the target
for many antifungal medications. One of them is a broad-spectrum anti-fungal drug called
Amphotericin B. Amphotericin B works by binding to ergosterol in the fungal cell membrane and forming
pores that cause rapid leakage of intracellular ions ultimately leading to fungal cell death.
In addition to its fungicidal activity, unfortunately Amphotericin B can also bind
to cholesterol molecules found in human cell membranes, although with relatively
lower affinity. This however has major adverse consequences because binding to cholesterol
also leads to the formation of pores that increase membrane permeability particularly in the renal
vasculature and renal epithelial cells, which can ultimately lead to nephrotoxicity.
Because of this, Amphotericin B is typically reserved only for treatment of severe systemic
infections that require a rapid response. Now, another antifungal that also binds
to ergosterol causing leakage of intracellular components is a drug called Nystatin. Although
Nystatin has the same mechanism of action as Amphotericin B, Nystatin is more toxic and because
of that it is not used systemically. Nystatin is also not absorbed from mucous membranes and skin,
which is why its use has been largely limited to the treatment of superficial Candida infections
of the mouth, skin, intestinal tract and vagina. All right, so besides targeting ergosterol itself,
many other antifungal drugs have been designed to target enzymes involved in ergosterol
biosynthesis. Now, the ergosterol biosynthesis in fungi utilizes a compound called squalene as
a starting material. In the presence of an enzyme called squalene epoxidase, squalene is transformed
into lanosterol, which in the presence of a cytochrome P450 enzyme called 14α-demethylase,
is subsequently converted to ergosterol. Now fungal squalene epoxidase is the target of a group
of potent antifungals called allylamines, which include drugs such as Naftifine and Terbinafine,
as well as allylamine derivative drug called Butenafine.
The next enzyme, 14α-demethylase is the target of a group of antifungals called azoles, which
include drugs such as Clotrimazole, Fluconazole, Itraconazole, Ketoconazole, Miconazole,
and Voriconazole. Now, by inhibiting squalene epoxidase and 14α-demethylase, allylamines and
azole antifungal agents deplete cell membrane ergosterol thereby impairing membrane fluidity,
leading to accumulation of toxic sterols, and ultimately causing fungal cell death.
That being said, both squalene epoxidase and 14α-demethylase are also present in human cells,
and although human enzymes are less affected than the fungal enzymes, there is still a potential for
non-targeted inhibition, which can lead to many adverse effects. One of the prime examples of this
is the non-targeted inhibition of human drug-metabolizing cytochrome
P450 enzymes by azoles, which is responsible for many pharmacokinetic drug interactions.
Now, in addition to ergosterol, another unique component of the fungal cell wall, which also
serves as an attractive pharmacological target for antifungal drugs is beta-glucan. Specifically,
some antifungal drugs have been designed to target an enzyme located in the fungal plasma
membrane that is responsible for the production of β(1-3)-glucans called β-(1,3)-glucan synthase. The
class of compounds known as echinocandins inhibits β-glucan synthase, which leads to a decrease
of β-glucans in the cell wall thereby causing osmotic instability, and ultimately cell lysis.
The example of drugs that belong to this class are; Anidulafungin, Caspofungin, and Micafungin.
Now, the major advantages of echinocandins relative to other antifungals include their
activity against azole-resistant Candida strains as well as Aspergillus species.
Furthermore, because the enzyme system for beta-glucan synthesis
is absent in human cells, unlike the other antifungals,
echinocandins have relatively low potential for toxicity or serious drug interactions.
Finally before we end, I wanted to briefly mention couple more antifungal drugs that
you may encounter in clinical practice, that is; Griseofulvin and Flucytosine. So unlike the
cell-wall-targeting antifunglas that we discussed thus far, Griseofulvin and Flucytosine work by
disrupting fungal cell division via mechanisms similar to cancer chemotherapeutic agents.
Specifically, Griseofulvin binds to tubulin, disrupting microtubule function
and inhibiting fungal cell mitosis, while Flucytosine works at the nucleus level where
it is converted into 5-fluorouracil and then to other active metabolites
that inhibit fungal RNA and DNA synthesis. And with that I wanted to thank you for watching,
I hope you found this video useful and as always stay tuned for more.