Download Antifungal Disruption of Cell Membrane

Anti-Fungal Compounds
• Eukaryotic pathogens
– Similar cell structure and function
• Many fungi are opportunistic
– Fungal infections on the rise
• Most have detoxification systems
• Fungal infections (mycoses) may be:
– Cutaneous
• Dermatophytic
– Subcutaneous
– Systemic
Antifungal Disruption of Cell Membrane
• many target membrane sterols (ergosterol)
• Polyenes
– Produced by Streptomyces
– Toxicity is a serious issue
– Amphotericin B
• Used for systemic mycoses
– Nystatin
• Effective topical treatment for cutaneous and
subcutaneous mycoses
• Azoles
– Synthetic drugs
– Fluconazole & Ketoconazole
– Used to treat systemic mycoses, dermatophytic
infections, cutaneous mycoses
Anti-fungal Inhibition of Cell Wall
Synthesis
• Inhibition of β-glucan results in incomplete cell wall
• Echinocandins
– Caspofungin
– used against many opportunistic mycoses
• Candida, Aspergillus and Pneumocystis
Anti-fungal Inhibition of Nucleic Acids
• Work on specific enzymes not in mammalian cells
• Fluorocytocine
–
–
–
–
Synthetic drug
Cytosine analog interferes with RNA synthesis
Serious toxicity issues
Used to treat systemic yeast infections
Other Anti-fungals
• Griseofulvin
– Given orally; reaches target site through sweat
– Inhibits cell division
• Tolnaftate
– Used for athlete's foot; action unknown
Anti-protozoan Inhibition of Nucleic Acids
• Nitroimidazoles
– Metronidazole
• Effective against Trichomonas and Girardia
• Effective against anaerobic bacteria
• Activated by anaerobic metabolism
• Alters DNA
• Side effect – black, hairy tongue
• Causes birth defects; passed in breast milk
Anti-protozoan Inhibition of Necessary
Metabolites
• Nifurtimox
– Effective against Trypanosoma
– Interferes with electron transport
– Mild gastrointestinal upset
Other Anti-protozoan Drugs
• Quinine and Quinolines
– Isolated from a Peruvian tree; replaced with
synthetic versions
– Exact mechanism of action unknown- inhibits
protozoan metabolism
– Chloroquine & mefloquine
• Malaria treatment
Anti-helminthic Drugs
• Niclosamide
– Prevents ATP generation
• Tapeworms
• Praziquantel
– Causes tetanic contractions
• Flukes
• Ivermectin
– Paralyzes worm
• Intestinal roundworms and tissue nematodes
Anti-viral Drugs
• Available antiviral drugs
effective specific type of virus
– None eliminate latent viruses
–
–
–
–
–
–
Attachment
Un-coating
Nucleic acid synthesis
Protein synthesis
Maturation
Release
Anti-viral Inhibition of Nucleic Acids
• Nucleoside/nucleotide analogs
– Results in an increased mutation rate
• Azidothymidine (AZT)
– HIV
• Ribavirin
– Flu, respiratory syncytial virus, hepatitis
• Acyclovir
– Reduces frequency and severity of herpes outbreaks
– Herpes viruses
Anti-viral Inhibition of Viral Proteins
• Indinavir
– Protease inhibitor- inhibit viral assembly/release
• HIV
• Amantadine
– Inhibit viral un-coating
• Flu
• Zanamivar
– Neuraminidase inhibitor- inhibit viral attachment
• Flu
Anti-microbial Resistance
•
•
Mutations lead to resistance
Resistance is transferred between cells
– Resistance genes are often on plasmids or
transposons
•
•
Multi-drug-resistant pathogens
Cross resistance
• Mechanisms of antibiotic resistance
1. Drug inactivating enzymes
2. Decreased uptake of the drug
3. Alteration of target molecule
4. Increased elimination of the drug
5. Protecting the target
• Misuse selects for resistant mutants
– Using outdated, weakened antibiotics
– Using antibiotics for inappropriate conditions
– Use of antibiotics in animal feed
– Failure to complete the prescribed regimen
• Slowing emergence and spread of resistance
– Responsibilities of healthcare workers
• Increase efforts to prescribe antibiotics for specific
organisms
• Educate patients on proper use of antibiotics
• Synergism
– Responsibilities of patients
• Follow instructions carefully
• Complete prescribed course of treatment