ANTI FUNGAL DRUGS AFFECTING CELL MEMBRANE AND CELL WALL. MOLECULAR MECHANISM OF DRUG ACTION

1. ANTI FUNGAL DRUGS AFFECTING
CELL MEMBRANE AND CELL WALL BIOSYNTHESIS
MOHAMMAD BILAL KAKAR
SCHOLAR
DEPARTMENT OF MICROBIOLOGY
MOLECULAR MECHANISM OF DRUG ACTION
UNIVERSITY OF BALOCHISTAN QUETTA.

2. Agenda
Infographic
Overview , General Characteristics
BREIF INTRO TO MYCOLOGY
01
Infections, structure of fungal cell
BRIEF INTRO TO FUNGAL INFECTION
02
ANTI FUNGAL AGENTS AFFECTING CELL WALL
03
.
ANTI FUNGAL AGENTS AFFECTING CELL
MEMBRANE
04

3. INTRODUCTION TO MYCOLOGY
FUNGUS
• A Eukaryotic organisms. Neither a plants nor animals.
• Heterotrophic by absorption
• Reproduced by Spores.
• Primary carbohydrate storage is Glycogen.
MYCOLOGY
MYKES: GREEK WORD  MUSHROOMS
The discipline that deal with the study of Fungi.
SPECIES
• 120,000 species are described
• 1,700 new species described each year..
INTERNAL
• Cell wall contain Chitin.
• True Nuclei with Nuclear membrane with paired
Chromosomes.
• Divided By : Sexual , Asexual and Both Reproduction.
• Unicellular (BUDDING YEAST) or Multicellular
MICOLOGIST
Scientist who study Fungi.
MYCOSIS
Disease caused by Fungi in Animals or Humans by Fungi.
STRUCTURE
• Hyphae (Long Branching Filamentous Structure of
Fungus)
• Mycelium (Vegetative part of Fungus or Fungus like
bacterial Colony , Consisting of mass of branching,
Thread – Like Hyphae. (Shiro: Mass of Hyphae) (MOLDS)
• Thallus ( Plant body that is not differentiated Into stem
and leaves and lacks true roots and a vascular system).

4. INTRODUCTION TO FUNGI
FUNGAL DISEASE
• Not Highly contagious.
• Humans acquire from nature.
• Epidermis, hair & nails.
• Lower in case of contagious.
GROWTH
• All are chemoheterotrophs.
• Absorption of Nutrients by power Enzymes.
• Grow at lower PH 5
• Grow in High Salt and Sugar
SPECIES
CHARACTERISTICS
• Non vascular Organisms.
• Reproduce by means of spores.
• Produce both sexual and asexual spores depending on
the species condition.
• Typically non motile. Although a few like chytrids have
motile phase.
HETEROTROPHIC NATURE
• Present in soil that has great economically importance
in decaying dead organic matters
PATHOGENIC IN NATURE
• Only 100 species of fungi are human and animals
pathogens.
• Some are opportunistic pathogens
BASIC STRUCTURE
• Cell wall is rigid. (Chitin , Mannan and polysaccharides)
• Cell Membrane contain ergoterols.
Fungi are found all around the world and grow in a wide range of habitats, including deserts.
Most grow on land (terrestrial) environments, but several species live only in
aquatic habitats. Most fungi live in either soil or dead matter, and many are symbionts of
plants, animals, or other fungi.

5. FUNGAL DIVERSITY

6. CLASSIFICATION OF FUNGAL INFECTION
CUTANEOUS &
SUBCUTANEOUS
SUPER
FICIAL
SYSTEMIC OPPORTUNISTIC
• These
are superficial cosmetic
fungal infections of the skin
or hair shaft.
• No living tissue is invaded
and there is no cellular
response from the host.
• Essentially no pathological
changes are elicited.
• Infection of skin and its
appendages (nail & hairs.
• Subcutaneous Infections
produce chronic
inflammation of
subcutaneous tissues
(sporotrichosis)
Systemic mycoses are
fungal infections affecting
internal organs. In the
right circumstances the
fungi enter the body via
the lungs, through the
gut, paranasal sinuses or
skin.
• Do not normally cause
diseases in healthy
people.
• Cause disease in in
immuno-compromised
People.
• Drug that suppress
immune system.
• Cancer therapy
• HIV Infection
• Cancer

7. FIGURES
SUPERFICIAL CUTANEOUS/ SUB-CUTANEOUS
SYSTEMIC OPPORTUNISTIC

8. FUNGAL INFECTION
If We look at the CDC’s web site that lists
diseases and conditions,
36% of the diseases have a bacterial origin,
33% have a viral origin,
6% are fungal,
25% are due to parasites

9. FUNGAL CELL STRUCTURE

10. STRUCTURE AND COMPOSTION OF FUNGAL CELL WALL
Fungal cell walls are dynamic structures that are essential for
protection of cellular contents, cell viability and pathogenesis.
Fungal cell walls contain:
CHITIN CHITOSAN
Β-1,3-GLUCAN Β-1,6-GLUCAN
Mixed Β-1,3/B-1,4-GLUCAN
MELANIN GLYCOPROTEINS
α- 1,3-GLUCAN

11. BIOSYNTHESIS OF CHITIN
The chitin is mediated by chitin synthase, that catalyzes the transfer of
N-acetylglucosamine from UDP-N-acetylglucosamine to a growing chitin chain.
Chitin  Polymer of N-acetylglucoseamine
CHITIN SYNTHASE
An enzyme that synthesis a
Chain of chitin in the fungal
Cell wall.

12. CHITIN SYNTHESIS A TARGET FOR ANTI-FUNGAL AGENT
The best-known chitin synthesis inhibitors are Nikkomycins and polyoxins.
The nikkomycins and polyoxins are substrate analogs of the chitin synthase
(Competitive Inhibitors).
However, they are not effective in
Controlling mycoses due to their
Limited uptake in the cytoplasm.

13. BIOSYNTHESIS OF B-GLUCAN
The B-Glucans comprise a group of B-D-Glucose Polysaccharides Naturally Occurring in
the cell wall of Fungi.
B-Glucan is synthesized by an Enzyme called
B-Glucan Synthase which is present in the
Fungal Cell Membrane.
Beta-Glucan Makes 50% of the Fungal Cell Wall.

14. GLUCAN SYNTHESIS A TARGET FOR ANTI-FUNGAL AGENTS.
The Inhibition of B-Glucan synthesis has been Extensively pursued as a means of
disrupting fungal growth and cell wall formation. This results in cell permeability and
Cell Lysis.
The Echinocandins are non-Competitive inhibitors of the B-Glucan Synthase.
Although Not Fully Understood the Echinocandins are known to bind the Glucan
Synthase.
Treatment with the Echinocandins is a promising therapy for Aspergillosis and
Candidiasis.
Echinocandins Caspofungin  Micafungin/Anidulafungin

15. FUNGAL CELL MEMBRANE
The plasma membrane provides protection to the fungal cell and their components.
The plasma membrane is made up of phospholipid bi-layer, carbohydrates and proteins.
Fungal cell membrane and mammalian cell membrane is different in lipid composition.
Mammalian cell  sterols (Cholesterol)
Fungal cell  ergosterols.

16. 14-ALPHA STEROL-
DEMETHYLASE
SQUALENE
EPOXIDASE
SYNTHESIS OF ERGOSTEROL
SQUALENE
Cytoplasm of fungi
ERGOSTEROL
SQUALENE EPOXIDE
LANOSTEROL

17. CELL MEMBRANE A TARGET FOR ANTI-FUNGAL AGENTS.
TERBINAFINE (Antifungal)
 Target = Inhibits Squalene Epoxidase
 Stop squalene Epoxide synthesization which results in failure of biosynthesis of Ergosterol Pathway.
SQUALENE
EPOXIDASE
SQUALENE
Cytoplasm of fungi
SQUALENE EPOXIDE
TERBINAFINE

18. CELL MEMBRANE A TARGET FOR ANTI-FUNGAL AGENTS.
AZOLES (Antifungal)
 Target = Inhibits 14-ALPHA STEROL-DEMETHYLASE
 Stop Ergosterol synthesization which results in failure of making cell membrane.
14-ALPHA STEROL-
DEMETHYLASE
ERGOSTEROL
LANOSTEROL
AZOLES

19. AZOLES

20. CELL MEMBRANE A TARGET FOR ANTI-FUNGAL AGENTS.
POLYENES (Antifungal)
Amphipathic in nature
Target cell membrane.
Forms canal like structure.
Increase permeabilization.
1. Amphotericin B
2. Nystatin
3. Natamycin

21. OTHER ANTIFUNGAL DRUGS
Flucytosine  Inhibit DNA Synthesis
Griseofulvin Inhibits Microtubules Inhibits Cell Division
Tavaborol Inhibit RNA Synthase  inhibits Protein Synthesis