Antifungal drugs

1. PHAR 532
LECTURE 11
ANTIFUNGAL DRUGS
Antimicrobial agents and
Immunization

2. Fungal infections
Fungi are eukaryotic cells, therefore drugs that affect
fungal cells are also toxic for human cells.
Fungi also have detoxification systems that modify
many antifungal agents.
Human fungal infections have increased
dramatically in incidence and severity in recent
years, owing mainly to advances in surgery, cancer
treatment, treatment of patients with solid organ and
bone marrow transplantation, the HIV epidemic, and
increasing use of broad-spectrum antimicrobial
therapy in critically ill patients

3. Fungal infections
Subdivided into:
 Superficial mycoses
 Systemic mycoses

4. Date of download: 12/3/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.
Sites of action of antifungal drugs. Amphotericin B and other polyenes (e.g., nystatin) bind to ergosterol in fungal cell membranes and increase membrane permeability. The imidazoles and triazoles (itraconazole, et
al.) inhibit 14-α-sterol demethylase, prevent ergosterol synthesis, and lead to the accumulation of 14-α-methylsterols. The allylamines (e.g., naftifine and terbinafine) inhibit squalene epoxidase and prevent ergosterol
synthesis. The echinocandins, such as caspofungin, inhibit the formation of glucans in the fungal cell wall.
Legend:
From: Antifungal Agents
Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e, 2016
From: Antifungal Agents
Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e, 2016

5. Systemic drugs
AMPHOTERICIN B. Amphotericin B is an
amphoteric polyene macrolide with broad spectrum
antifungal activity.
MECHANISM OF ACTION. Amphotericin B binds to
a sterol moiety, primarily ergosterol in the
membrane of sensitive fungi. By virtue of their
interaction with these sterols, polyenes appear to
form pores or channels that increase the
permeability of the membrane, allowing leakage of a
variety of small molecules

6. Amphotericin B

7. Amphotericin B
Amphotericin B has useful clinical activity against
Candida spp., Cryptococcus neoformans,
Blastomyces dermatitidis, Histoplasma capsulatum,
Sporothrix schenckii, Coccidioides spp.,
Paracoccidioides braziliensis, Aspergillus spp.,
Penicillium marneffei.
Resistance is rare

8. Flucytosine
Flucytosine (5-fluorocytosine) has a spectrum of
antifungal activity that is considerably more
restricted than that of amphotericin B.
It interferes with nucleic acids synthesis.
The selective action of flucytosine is due to the lack
of cytosine deaminase in mammalian cells, which
prevents metabolism to fluorouracil.

9. Date of download: 12/3/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.
Action of flucytosine in fungi. Flucytosine (5-fluorocytosine) is transported by cytosine permease into the fungal cell, where it is deaminated to 5-fluorouracil (5-FU). The 5-FU is converted to 5-fluorouracil-ribose
monophosphate (5-FUMP) and then is either converted to 5-fluorouridine triphosphate (5-FUTP) and incorporated into RNA or converted to 5-fluoro-2′-deoxyuridine-5′-monophosphate (5-FdUMP), a potent inhibitor
of thymidylate synthase. 5-FUDP, 5-fluorouridine-5′-diphosphate; dUMP, deoxyuridine-5′-monophosphate; dTMP, deoxythymidine-5′-monophosphate; PRT, phosphoribosyltransferase.
Legend:
From: Antifungal Agents
Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e, 2016
From: Antifungal Agents
Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e, 2016

10. Activity and resistance
Activity: Flucytosine has clinically useful activity
against C. neoformans, Candida spp., and the agents
of chromoblastomycosis.
Resistance: Drug resistance can arise during therapy
(secondary resistance) and is an important cause of
therapeutic failure when flucytosine is used alone for
cryptococcosis and candidiasis. The mechanism for
this resistance can be loss of the permease necessary
for cytosine transport or decreased activity of either
UPRTase or cytosine deaminase

11. Imidazoles and triazoles
The major effect of imidazoles and triazoles on fungi
is inhibition of 14-α-sterol demethylase.
Imidazoles and triazoles thus impair the
biosynthesis of ergosterol for the cytoplasmic
membrane and lead to the accumulation of 14-α-
methylsterols. These methylsterols may disrupt the
close packing of acyl chains of phospholipids,
impairing the functions of certain membrane-bound
enzyme systems, thus inhibiting growth of the fungi.

12. Resistance
Azole resistance emerges gradually during prolonged
azole therapy, causing clinical failure in patients with
far-advanced HIV infection and oropharyngeal or
esophageal candidiasis. The primary mechanism of
resistance in C. albicans is accumulation of
mutations in ERG11, the gene coding for the 14-α-
sterol demethylase; cross-resistance is conferred to
all azoles.

13. Echinocandins
Echinocandins inhibit formation of 1,3-β-D-glucans
in the fungal cell wall, reducing its structural
integrity

14. Date of download: 12/3/2016 Copyright © 2016 McGraw-Hill Education. All rights reserved.
The action of echinocandins. The strength of the fungal cell wall is maintained by fibrillar polysaccharides, largely β-1,3-glucan and chitin, which bind covalently to each other and to proteins. A glucan synthase complex in the plasma membrane catalyzes the
synthesis of β-1,3-glucan; the glucan is extruded into the periplasm and incorporated into the cell wall. Echinocandins inhibit the activity of the glucan synthase complex, resulting in loss of the structural integrity of the cell wall. A subunit of glucan synthase
designated Fks1p is thought to be the target of the echinocandin. Mutations in Fks1p, coded by FSK1, cause resistance to echinocandins.
Legend:
From: Antifungal Agents
Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e, 2016
From: Antifungal Agents
Goodman and Gilman's Manual of Pharmacology and Therapeutics, 2e, 2016

15. Topical treatments
Imidazoles and triazoles can be used for both topical
and systemic infections