BSC 283/283L Microbiology - Antimicrobial Drugs

BSC 283/283L Announcements

By the end of this chapter, students should be able to:

Describe the difficulties of developing drugs against viruses and eukaryotic pathogens.
List potential points in viral replication that antiviral drugs may target.
Provide examples of antifungal agents, describe the fungal infections they may treat, and discuss how they target fungi.
Describe antiprotozoal drugs—including examples, mechanisms of action, and therapeutic applications.
Discuss the main antihelminthic drugs, their mechanisms of action, and medical applications.

Challenges arise from the need to create drugs that specifically target viruses and eukaryotic pathogens while minimizing damage to human cells.
Antiviral drugs can be classified into five main categories based on the viral activities they target:
- Attachment: Prevents virus from attaching to host cell.
- Penetration: Prevents virus from entering host cell.
- Uncoating: Disrupts the virus to release its genetic material.
- Viral replication and assembly: Interferes with the multiplication of virus.
- Viral release: Aids in preventing new virions from leaving the host cell.
A sixth category involves drugs that stimulate immune responses against viruses, such as interferons.

Antiviral medications are primarily effective when viruses are actively replicating, making latent viruses difficult to treat.
Historically, most antiviral therapies have been focused on:
- Human immunodeficiency virus (HIV)
- Certain herpes family viruses
- Hepatitis viruses
- Influenza viruses
In 2020, Remdesivir was the first antiviral drug approved by the U.S. FDA to treat COVID-19.

Most antifungal agents are designed to affect:
- Fungal cell walls
- Fungal plasma membranes
- Fungal nucleic acid synthesis

Fungal cell membranes contain ergosterol, a sterol not present in human cells.
Three primary classes of antifungal drugs target fungal plasma membranes:
- Azoles: Inhibit enzymes involved in ergosterol synthesis.
- Examples: Fluconazole, Ketoconazole
- Treat conditions such as athlete’s foot, ringworm, and yeast infections.
- Allyamines: Also inhibit enzymes that aid in ergosterol production.
- Examples: Terbinafine, Naftifine
- Treat similar conditions (athlete’s foot, ringworm, yeast infections).
- Polyenes: Directly interact with ergosterols, making plasma membranes permeable and leading to cell lysis.
- Have a narrow therapeutic index and can cause side effects, especially nephrotoxicity.
- Examples:
  - Nystatin: Too toxic for systemic use; applied topically (cutaneous candidiasis).
  - Amphotericin B: Effective against most pathogenic fungi and reserved for severe systemic fungal infections.

Echinocandin drugs target the enzyme responsible for synthesizing beta-glucan, crucial for fungal cell wall integrity.
- Predominantly used against systemic fungal infections in immunocompromised patients.
- Example: Caspofungin acetate.

Flucytosine: Impedes fungal DNA replication and transcription.
- Converted into a nucleic acid analog that obstructs DNA and RNA synthesis.
- Typically utilized alongside amphotericin B for treatment of severe infections like Cryptococcus meningitis and systemic candidiasis.

Development of effective drugs is complicated due to:
- The eukaryotic nature of the parasites.
- Their complex life cycles, wherein targeting one stage may not affect others.

There is a prevalent misconception in developed nations that protozoan parasites are not a health concern.
Nonetheless, millions in developed countries are infected:
- Approximately 3.7 million people have trichomoniasis.
- 30 million Americans are chronically infected with Toxoplasma gondii.

Antimalarial Drugs: Focused on targeting Plasmodium species responsible for malaria.
- Six main classes include:
- Aminoquinolines
- Arylaminoalcohols
- Artemisinins
- Respiratory chain inhibitors
- Antifolates
- Cross-over antibacterial drugs (e.g., doxycycline, clindamycin)
Nonmalarial Antiprotozoan Drugs: Specifically target protozoan infections other than malaria.

Chloroquine: Most commonly used, increasingly resistant.
Hydroxychloroquine: Similar usage context as chloroquine.
Quinine: One of the earliest treatments for malaria; resistance is also increasing.

Used to combat resistant strains of malaria, consisting of an artemisinin-class drug (commonly artesunate) in conjunction with one or more nonartemisinin drugs.
Artemisinin originates from the herb wormwood; resistance is still rare.

Metronidazole (Flagyl): A nitroimidazole that targets nucleic acids and is effective against:
- Toxoplasma gondii (toxoplasmosis)
- Trichomonas vaginalis (trichomoniasis)
- Giardia lamblia (giardiasis)
- Entamoeba histolytica (amoebiasis)
Trimethoprim-sulfamethoxazole (TMP/SMX): An antifolate combination blocking folate production in certain protozoans and bacteria; effective against:
- Toxoplasma gondii
- Giardia
- Cryptosporidium
- Entamoeba
Nitrazoxanide: Disrupts anaerobic energy metabolism in protozoa, effective against:
- Giardia
- Cryptosporidium
- Certain parasitic worms.

Albendazole and mebendazole: Broad-spectrum antihelminthic agents that interfere with glucose uptake in worms by targeting their microtubules; effective against various roundworms (e.g., Ascaris, hookworms, pinworms, Trichinella, and certain tapeworms).
Praziquantel (Bilticide): A drug that paralyzes parasites, which are then expelled through the feces; effective against flukes and tapeworms.