In clinical work, we often face a variety of antifungal drugs, and because there are too many choices, there is often confusion. Today, we bring you an overview of antifungal drugs from antifungal action mechanisms, antifungal activity of drugs and adverse drug reactions!
Fungal cell structure
The fungus belongs to eukaryotic cells, has a nuclear pore complex, and has cytoskeletal microfilaments and various organelles in the cytoplasm.
The main material of the cell wall is carbohydrates, including some crystalline substances such as α-glucan, chitin, β-(1,3) glucan combined N-acetylglycine polymer. Others such as mannan and the like.
(Chitin: the main component of fungal fluorescent staining; mannan-GM experiment is mainly used for serological detection of Aspergillus).
These include phospholipids, ergosterol, glucan synthase, and the like.
Main antifungal mechanism of action
1. Azole mechanism
Azole drugs include fluconazole, itraconazole, fluconazole, and posaconazole.
Ergosterol is a major component of cell membrane sterols in many fungi. By inhibiting 14α-sterol demethylase (lanosterol demethylase), a fungal cytochrome P450 (CYP)-dependent enzyme, azole drugs prevent cell membrane ergosterol from normal synthesis, damage Fungal cell membranes that cause fungal death.
The structure of the 14α-demethylase site and the azole drug mainly affects the affinity of the drug to the target enzyme, and for some fungal species, the azole can produce cross-resistance. The extended non-polar side chain of itraconazole and posaconazole enhances binding to 14α-demethylase, so the antibacterial spectrum is also broader. Voriconazole is a derivative of fluconazole, but its structure has an α-0-methyl group, so it can resist Aspergillus and other filamentous fungi.
Triazole drug resistance is mainly due to azole binding pocket of 14α-demethylase, and fluconazole resistance is related to overexpression of MDR1 efflux pump. Pumping CDR1 and CDR2 can cross-resist azoles. The natural resistance of Candida krusei to fluconazole is associated with impaired binding of the drug to 14α-demethylase, and new azoles enhance this binding. Resistance to fluconazole by Candida glabrata is usually the result of over-expression of efflux pumps, and therefore, cross-resistance of azoles is often produced.
2. Terbinafine mechanism
Similar to azoles, terbinafine inhibits squalene epoxidase to inhibit the synthesis of ergosterol. Terbinafine is mainly distributed in the skin and nail bed, while the plasma concentration is relatively low, generally used for A and skin fungal diseases.
3. Mechanism of action of amphotericin B
AMB combines directly with ergosterol to form a complex and form pores that cause leakage of intracellular material. Amphotericin B affects ergosterol-rich cell membranes and cholesterol-rich cell membranes (mammals and humans), so it can cause toxic side effects, such as kidney enrichment, causing kidney damage. Amphotericin B can also release pro-inflammatory cytokines, leading to fever and chills during the infusion process. The amphotericin B lipid-containing compound preparation can reduce the distribution of kidneys and reduce the side effects. AMB clinical resistance is rare, sterol substitution and production of neutralizing enzymes to tolerate oxygen damage are the main mechanisms of AMB natural resistance and acquired resistance.
4. Mechanism of action of echinomycin
Echinomycin acts on the fungal cell wall and inhibits the synthesis of β-(1,3)-d-glucan, one of the major structures of the cell wall, by inhibiting β-(1,3)-d-glucan synthase. effect. The synthesis process of β-1,3-d-glucan in the cell wall and the expression of the enzyme mainly determine the antifungal spectrum of echinomycin. Echinocandins have good activity against Candida and Aspergillus. Rarely resistant, the main catalytic subunit changes of β-(1,3)-d-glucan synthase caused by FKS1 and FKS2 mutations in the "hot spot" zone can lead to decreased echinocanin action, elevated MICs and treatment failure. .
Flucytosine enters fungal cells via cytosine permease and is metabolized to fluorouracil by cytosine deaminase, which replaces uracil and causes false coding of fungal RNA. However, the intestinal flora can also convert 5-fluorocytosine to 5-fluorouracil, leading to adverse reactions such as nausea, vomiting, diarrhea, and myelosuppression. However, cytosine permease and cytosine deaminase mutations are prone to occur, so flucytosine is generally only used for combination therapy.