Antifungal Inhibitors and Drugs
Antifungal inhibitors
Komal Pareek
1
Challenge
•
Eukaryotes
•
Difficult to find selective toxicity in eukaryotes than prokaryotes
•
Fungal infections r more frequent as opportunistic infections in
immunocompromised
•
Cell membrane essential component- sterol
Fungi-Ergosterol
Higher animals- cholesterol
2
Antifungal inhibitors
•
Agents affecting Fungal Sterols
Polyenes-Amphotericin B, Nystatin
Azoles- Voriconazole
•
Agents affecting Fungal cell walls
•
Echinocandins
•
Agents inhibiting Nucleic acid-flucytocine
•
Other Antifungal drugs-Griseofulvin
3
A
n
t
i
f
u
n
g
a
l
D
r
u
g
s
•
Polyenes
, such as
nystatin
and
amphotericin B,
for
systemic fungal infections. Inhibition of ergosterol
synthesis
fungicidal. Nephrotoxic
•
Griseofulvin
from
Penicillium.
Systemic/oral. Binds to
tubulin
F
or
Tineae
4
Antimycotic Antibiotics
Polyenes
Broad spectrum. Some effect on certain protozoa.
Isolated,
Streptomyces
sp.
Binds to sterols in fungal cell membrane; cell leaks K
+
, P
H
drops , small org. molecules
•
Macrolaktone [26 eor
38
-ring, Larger than macrolides ( erytromycin etc)]
•
Polyene (Macrolides not polyenes)
•
Several OH-groups
•
amino sugar,
•
Bad water solibility.
5
•
Amfotericin B
•
Systemic infect (infusion)
•
Somewhat less toxic.
•
Clinical treatment for systematic fungal diseases-histoplasmosis,
coccidiomycosis and blastomycosis
•
Toxicity-to kidney- strong limiting factor in use
•
Administering the drug
encapsulated in lipids(liposomes)
appears to
minimize toxicity
6
Nystatin A
•
Toxic, Topical(Local) treatment,
Nystatin
(originally named
Fungicidin
) is a
polyene
antifungal medication
that is derived
from a bacterium,
Streptomyces noursei
.
•
Many
mold
and
yeast infections
are sensitive
to nystatin, most notably
Candida
.
•
It is used primarily for infections involving
the skin, mouth, oesophagus, and vagina
7
Synthetic Antifungals
Azoles
•
Inhibit the synthesis of sterol components
of fungal membrane
•
Removes methyl group from lanosterol
•
Azoles reduces ergosterol level….leads to
loss of cytoplasmic constituents
•
Side effects- reduces cholesterol synthesis
8
Voriconazole
•
Replaced Amphotericin B for systematic
fungal infection
•
Treatment of Aspergillosis of the CNS….is
able to penetrate the blood –brain barrier
Ketokonazol
:
•
Orally-used for systematic fungal infections
•
Less toxic than Amphotercic B
•
Occasional liver damage
•
Topical ointment to treat dermatomycocses
2 or 3 other
aromatic rings
9
Griseofulvin
•
Produced by
Penicillium griseofulvin
•
Active against superficical dermatophytic fungal infection of the
hair(tinea capitis or ringworm) and nails even though it’s route of
administration is oral.
•
It specifically binds to the keratin found in skin, hair follicles and nails
•
It’s mode of infection –
to block microtubules assembly
which
interfere with
mitosis
and thereby inhibits fungal reproduction
10
A
n
i
d
u
l
a
f
u
n
g
i
n
•
It is a member of the class of antifungal drugs known as the
echinocandins
;
•
I
ts mechanism of action is by inhibition of
(1→3)-β-D-glucan
synthase, an enzyme important to the
synthesis of the
fungal cell wall
.
•
Glucan synthase is not present in mammalian cells,
so it is an
attractive target
for antifungal activity
.
11
•
Anidulafungin is manufactured via semisynthesis.
•
The starting material is
echinocandin B
(a
lipopeptide
) fermentation
product of
Aspergillus nidulans
•
Anidulafungin has proven efficacy against
esophageal candidiasis
, but
its main use will probably be in invasive
Candida
infection;
•
it may also have application in treating invasive
Aspergillus
infection.
12
In this detailed overview, we explore antifungal inhibitors and drugs, including their mechanisms of action, impact on eukaryotes and prokaryotes, common agents affecting fungal sterols and cell walls, as well as synthetic antifungals. From polyenes like nystatin to azoles such as voriconazole, this compilation provides valuable insights into the treatment of fungal infections. Additionally, antimycotic antibiotics and systemic antifungals like amphotericin B are discussed, shedding light on their uses and potential toxicities.
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Presentation Transcript
Antifungal inhibitors Komal Pareek 1
Challenge Eukaryotes Difficult to find selective toxicity in eukaryotes than prokaryotes Fungal infections r more frequent as opportunistic infections in immunocompromised Cell membrane essential component- sterol Fungi-Ergosterol Higher animals- cholesterol 2
Antifungal inhibitors Agents affecting Fungal Sterols Azoles- Voriconazole Polyenes-Amphotericin B, Nystatin Agents affecting Fungal cell walls Echinocandins Agents inhibiting Nucleic acid-flucytocine Other Antifungal drugs-Griseofulvin 3
Antifungal Drugs Antifungal Drugs Polyenes, such as nystatin and amphotericin B, for systemic fungal infections. Inhibition of ergosterol synthesis fungicidal. Nephrotoxic Griseofulvin from Penicillium. Systemic/oral. Binds to tubulin For Tineae 4
Antimycotic Antibiotics Polyenes Broad spectrum. Some effect on certain protozoa. Isolated, Streptomyces sp. Binds to sterols in fungal cell membrane; cell leaks K+, PH drops , small org. molecules Macrolaktone [26 eor 38-ring, Larger than macrolides ( erytromycin etc)] Polyene (Macrolides not polyenes) Several OH-groups amino sugar, Bad water solibility. 5
OH OH O OH HO O HO OH HO HO O CO2H Amfotericin B Systemic infect (infusion) Somewhat less toxic. O O Amfotericin B OH NH2 OH Clinical treatment for systematic fungal diseases-histoplasmosis, coccidiomycosis and blastomycosis Toxicity-to kidney- strong limiting factor in use Administering the drug encapsulated in lipids(liposomes)appears to minimize toxicity 6
OH OH O OH HO O HO HO HO HO O Nystatin A Toxic, Topical(Local) treatment, CO2H O O NH2 OH Nystatin A OH Nystatin (originally named Fungicidin) is a polyene antifungal medication that is derived from a bacterium, Streptomyces noursei. Many mold and yeast infections are sensitive to nystatin, most notably Candida. It is used primarily for infections involving the skin, mouth, oesophagus, and vagina 7
Synthetic Antifungals Azoles N N N NN N H N H N H H Azol / Pyrrol 1,2-Diazol 1,2,4-Triazol 1,3-Diazol / Imidazol Inhibit the synthesis of sterol components of fungal membrane Removes methyl group from lanosterol Azoles reduces ergosterol level .leads to loss of cytoplasmic constituents Side effects- reduces cholesterol synthesis 8
Ketokonazol: Orally-used for systematic fungal infections Less toxic than Amphotercic B Occasional liver damage Topical ointment to treat dermatomycocses Cl Cl O O O N N N O N Voriconazole Replaced Amphotericin B for systematic fungal infection Treatment of Aspergillosis of the CNS .is able to penetrate the blood brain barrier "cis", [ ] 2 or 3 other aromatic rings 9
Griseofulvin Produced by Penicillium griseofulvin Active against superficical dermatophytic fungal infection of the hair(tinea capitis or ringworm) and nails even though it s route of administration is oral. It specifically binds to the keratin found in skin, hair follicles and nails It s mode of infection to block microtubules assembly which interfere with mitosis and thereby inhibits fungal reproduction 10
Anidulafungin Anidulafungin It is a member of the class of antifungal drugs known as the echinocandins; Its mechanism of action is by inhibition of (1 3)- -D-glucan synthase, an enzyme important to the synthesis of the fungal cell wall. Glucan synthase is not present in mammalian cells, so it is an attractive target for antifungal activity. 11
Anidulafungin is manufactured via semisynthesis. The starting material is echinocandin B (a lipopeptide) fermentation product of Aspergillus nidulans Anidulafungin has proven efficacy against esophageal candidiasis, but its main use will probably be in invasive Candida infection; it may also have application in treating invasive Aspergillus infection. 12
