Introduction to Antifungal, Antiprotozoal, Anthelmintic Agents & Sulfonamides
This unit covers four distinct categories of anti-infective agents. Antifungal agents — from polyene antibiotics (Amphotericin B) that bind ergosterol to azole antifungals (Fluconazole, Ketoconazole) that inhibit its synthesis. Antiprotozoal agents — Metronidazole-class nitroimidazoles. Anthelmintic agents — benzimidazoles (Albendazole) and macrocyclic lactones (Ivermectin). Sulfonamides — the first synthetic antibacterials with a rich SAR and the concept of sequential folate blockade (Cotrimoxazole).
Syllabus & Topics
- 1Antifungal Antibiotics – Amphotericin B: Polyene macrolide from Streptomyces nodosus. Structure: large 38-membered macrolide ring with 7 conjugated double bonds (polyene → yellow color) + a mycosamine sugar. MOA: binds to Ergosterol in fungal cell membrane → forms pores/channels → leakage of K⁺, Na⁺, H⁺ → cell death. Selectivity: fungi have ergosterol, mammals have cholesterol (lower binding affinity, but not zero → toxicity). Gold standard for severe systemic fungal infections. Major ADR: nephrotoxicity (dose-limiting), infusion-related reactions (fever, chills). Lipid formulations (liposomal AmB) reduce toxicity.
- 2Nystatin & Natamycin: Nystatin: polyene similar to Amphotericin B but too toxic for systemic use → topical only (oral thrush, vaginal candidiasis). Named after New York State Health Dept where discovered. Natamycin (Pimaricin): polyene, used topically for fungal keratitis (eye infections). Both share the same MOA as Amphotericin B (ergosterol binding → pore formation).
- 3Griseofulvin: From Penicillium griseofulvum. Structure: contains a grisan ring system with chlorine and methoxy groups. MOA: binds to fungal microtubule protein (tubulin) → disrupts mitotic spindle → inhibits fungal cell division (fungistatic). Also deposits in newly formed keratin → fungal growth in skin/nails/hair arrested. Used for dermatophyte infections (Trichophyton, Microsporum, Epidermophyton). Superseded by terbinafine/azoles for most indications. Induces CYP450 → drug interactions.
- 4Azole Antifungals – MOA & Classification: MOA: inhibit lanosterol 14α-demethylase (CYP51, a cytochrome P450 enzyme) → block conversion of lanosterol to ergosterol → depleted ergosterol + accumulation of toxic 14α-methyl sterols → disrupted membrane integrity. Imidazoles (two nitrogen atoms in ring): Clotrimazole, Miconazole, Ketoconazole, Econazole — mostly topical (except Ketoconazole oral). Triazoles (three nitrogens): Fluconazole, Itraconazole, Terconazole — systemic, more selective for fungal CYP51, fewer side effects.
- 5Important Azoles: Clotrimazole: imidazole, topical broad-spectrum (skin, vaginal candidiasis). Miconazole: imidazole, topical + oral gel. Ketoconazole: first oral azole antifungal, BUT hepatotoxic + inhibits human CYP450 and adrenal steroid synthesis (anti-androgenic) → largely replaced. Fluconazole: triazole, excellent oral bioavailability, water-soluble, penetrates CSF → drug of choice for cryptococcal meningitis and systemic candidiasis. Itraconazole: triazole, broader spectrum (Aspergillus), requires acidic pH for absorption. Naftifine: allylamine — inhibits squalene epoxidase (earlier step in ergosterol synthesis). Tolnaftate: thiocarbamate, topical antifungal, similar MOA to allylamines.
- 6Antiprotozoal Agents – Nitroimidazoles: Metronidazole: 5-nitroimidazole. MOA: the nitro group is reduced by anaerobic organisms (using ferredoxin/flavodoxin electron transport) → cytotoxic nitroso and hydroxylamine radicals → damage DNA (strand breakage) → cell death. Selective for anaerobes and microaerophilic protozoa (Entamoeba, Giardia, Trichomonas) because aerobic organisms cannot reduce the nitro group effectively. Also effective vs anaerobic bacteria (Bacteroides, C. difficile). ADR: metallic taste, disulfiram-like reaction with alcohol (blocks aldehyde dehydrogenase).
- 7Other Antiprotozoal Agents: Tinidazole: 2nd gen nitroimidazole, longer t½ → single-dose treatment. Ornidazole: no disulfiram reaction (safe with alcohol). Diloxanide furoate: luminal amebicide — no effect on tissue trophozoites, kills cysts in the intestinal lumen. Iodoquinol (Diiodohydroxyquin): 8-hydroxyquinoline, luminal amebicide. Pentamidine isethionate: diamidine, used for Pneumocystis pneumonia (PCP) in AIDS, early-stage African trypanosomiasis. MOA: possibly inhibits kinetoplast DNA. Eflornithine (DFMO): irreversible inhibitor of ornithine decarboxylase → blocks polyamine synthesis → effective vs T. brucei gambiense (sleeping sickness).
- 8Anthelmintics – Benzimidazoles: Mebendazole & Albendazole: benzimidazole carbamates. MOA: bind to β-tubulin of parasitic helminths → inhibit microtubule polymerization → disrupted glucose uptake and cell division. Albendazole: broader spectrum, better absorption → drug of choice for most intestinal and tissue helminths (ascariasis, hookworm, hydatid disease, neurocysticercosis). Thiabendazole: first benzimidazole anthelmintic, now largely replaced by albendazole.
- 9Other Anthelmintics: Diethylcarbamazine (DEC): piperazine derivative, drug of choice for lymphatic filariasis (Wuchereria bancrofti — elephantiasis). MOA: immobilizes microfilariae → phagocytosis by host immune system. Niclosamide: salicylanilide, kills tapeworms by uncoupling oxidative phosphorylation in scolex/proglottids. Praziquantel: isoquinoline, drug of choice for ALL schistosome species and most cestodes (tapeworms). MOA: increases Ca²⁺ permeability → spastic paralysis of worm → tegumental damage. Ivermectin: macrocyclic lactone from Streptomyces avermitilis. MOA: activates glutamate-gated Cl⁻ channels → paralysis of nematodes/arthropods. TOC for Onchocerciasis (river blindness) and Strongyloidiasis. Nobel Prize 2015 (Satoshi Ōmura).
- 10Sulfonamides – Historical & MOA: First synthetic antibacterials (Prontosil, Gerhard Domagk, Nobel Prize 1939). Prontosil = azo prodrug → reduced in vivo to active Sulfanilamide. MOA: competitive inhibitor of dihydropteroate synthase (DHPS) → block incorporation of PABA into dihydrofolic acid → ↓folate → ↓DNA synthesis. Selective toxicity: bacteria synthesize folate de novo (need DHPS); humans obtain folate from diet (no DHPS). Bacteriostatic.
- 11Sulfonamide SAR: Parent structure: p-aminobenzenesulfonamide. SAR: (1) Primary aromatic amine (–NH₂ at N-4): ESSENTIAL — must be free (or released in vivo). Acetylation → loss of activity (metabolic inactivation). (2) Sulfonamido group (–SO₂NH–): essential for activity (mimics –COOH of PABA). (3) N-1 substitution: heterocyclic ring → modulates potency, pKa, pharmacokinetics (protein binding, t½, excretion). No substitution at N-4 tolerated (except prodrug forms).
- 12Important Sulfonamides: Sulfamethoxazole: combined with Trimethoprim (Cotrimoxazole/Bactrim). Sulfadiazine: used with Pyrimethamine for toxoplasmosis. Sulfacetamide: topical ophthalmic (eye drops for conjunctivitis). Sulfasalazine: anti-inflammatory for ulcerative colitis/rheumatoid arthritis (prodrug → cleaved to 5-ASA + Sulfapyridine in colon). Silver Sulfadiazine: topical for burn wound infections. Mafenide acetate: topical burn dressing (penetrates eschar).
- 13Folate Reductase Inhibitors & Sequential Blockade: Trimethoprim: diaminopyrimidine, inhibits dihydrofolate reductase (DHFR) → blocks folate → tetrahydrofolate conversion. Selective: 50,000x more affinity for bacterial DHFR than mammalian DHFR. Cotrimoxazole (TMP-SMX): Trimethoprim + Sulfamethoxazole (1:5 ratio). Sequential blockade: SMX blocks step 1 (DHPS), TMP blocks step 2 (DHFR) → synergistic bactericidal effect. Used for UTI, PCP prophylaxis in HIV.
- 14Sulfones – Dapsone: 4,4′-Diaminodiphenylsulfone. MOA: same as sulfonamides (inhibits DHPS). Drug of choice for leprosy (Hansen’s disease) — part of WHO Multi-Drug Therapy (MDT: Dapsone + Rifampicin + Clofazimine). Also used for Dermatitis herpetiformis and PCP prophylaxis. ADR: methemoglobinemia, hemolytic anemia (especially in G6PD deficiency), dapsone hypersensitivity syndrome.
Learning Objectives
Exam Prep Questions
Q1. Why Is Amphotericin B Toxic to Human Cells as Well?
Amphotericin B works by binding to membrane sterols and forming pores in the cell membrane. Fungal cell membranes contain Ergosterol, which is the preferred binding target of the drug. However, human cell membranes contain Cholesterol, which has a similar structure. Although Amphotericin B has about ten times higher affinity for ergosterol, it can still bind cholesterol at therapeutic doses. This interaction damages human cell membranes, particularly in kidney tubular cells, leading to nephrotoxicity—the major dose-limiting adverse effect. Lipid-based formulations such as Liposomal Amphotericin B reduce toxicity by preferentially delivering the drug to fungal cells while limiting exposure to human tissues.
Q2. What Is the Difference Between Imidazole and Triazole Antifungals?
Imidazole antifungals contain a five-membered ring with two nitrogen atoms. Examples include Clotrimazole and Ketoconazole.
Triazole antifungals contain a five-membered ring with three nitrogen atoms. Examples include Fluconazole and Itraconazole.
Triazoles are more selective for the fungal enzyme Lanosterol 14 alpha demethylase and have less inhibition of human cytochrome P450 enzymes. They also exhibit improved pharmacokinetic properties such as better oral absorption and better central nervous system penetration, particularly with fluconazole. Because they cause fewer endocrine side effects compared with ketoconazole, triazoles are generally preferred for systemic fungal infections.
Q3. Why Can’t Metronidazole Kill Aerobic Bacteria?
Metronidazole requires reduction of its nitro group to generate reactive free radicals that damage microbial DNA. This reduction step depends on low-redox electron-transport proteins such as Ferredoxin, which are present in anaerobic bacteria and certain protozoa. In aerobic organisms, oxygen rapidly re-oxidizes the reduced drug back to its inactive form before toxic radicals can accumulate. As a result, metronidazole shows selective activity against anaerobic microorganisms but not aerobic bacteria.
Q4. What Is Cotrimoxazole and Why Is It Synergistic?
Cotrimoxazole is a fixed combination of Trimethoprim and Sulfamethoxazole in a 1:5 ratio. The two drugs block sequential steps in bacterial folate synthesis. Sulfamethoxazole inhibits Dihydropteroate synthase, preventing the formation of dihydrofolic acid from PABA. Trimethoprim inhibits Dihydrofolate reductase, preventing conversion of dihydrofolic acid into tetrahydrofolic acid. Blocking two consecutive enzymatic steps leads to synergistic bactericidal activity because bacteria cannot produce the folate necessary for DNA synthesis.