Fungal cells

With the aid of cytosine permease, flucytosine reaches the fungal cell where it is converted by cytosine deaminase into 5-fluorouracil [51-21-8]. Cytosine deaminase is not present in the host, which explains the low toxicity of 5-FC. 5-Fluorouracil is then phosphorylated and incorporated into RNA and may also be converted into 5-fluorodeoxyuridine monophosphate, which is a potent and specific inhibitor of thymidylate synthetase. As a result, no more thymidine nucleotides are formed, which in turn leads to a disturbance of the DNA-synthesis. These effects produce an inhibition of the protein synthesis and cell repHcation (1,23,24). 5-Fluorouracil caimot be used as an antimycotic. It is poorly absorbed by the fungus to begin with and is also toxic for mammalian cells. 

A fungicidal effect is that which kills the fungal cell. Antifungal Dtugs... 

Fungistasis is the inhibition of fungal growth without killing the fungal cell. 

Griseofulvin (Grisactin) exerts its effect by being deposited in keratin precursor cells, which are then gradually lost (due to the constant shedding of top skin cells), and replaced by new, noninfected cells. The mode of action of flucytosine (Ancobon) is not clearly understood. Clotrimazole (Lotrimin, Mycelex) binds with phospholipids in the fungal cell membrane,... 

Mehta, R., Lopez-Berestein, G., Hopfer, R., Mills, K., and Juliano, R. L. (1984). Liposomal amphotericin B is toxic to fungal cells but not to mammalian cells. Biochim. Biophys. Acta, 770. 230-234. 

In contrast to the wide range of antibacterial antibiotics, there are very few antifungal antibiotics that can be used systemically. Lack of toxicity is, as always, of paramount importance, but the differences in structure of, and some biosynthetic processes in, fungal cells (Chapter 2) mean that antibacterial antibiotics are usually inactive against fungi. 

This synthetic allylamine derivative inhibits the enzyme squalene epoxidase at an early stage in fungal sterol biosynthesis. Acting as a structural analogue of squalene, naffidine causes the accumulation of this unsaturated hydrocarbon, and a decrease in ergosterol in the fungal cell membrane. 

Intrinsic (natural, innate) resistance. In one form of intrinsic resistance, the fungal cell wall (see Chapter 2) is considered to present a barrier to exclude or, more likely, to reduce the penetration by biocide molecules. The evidence to date is sketchy but the available information tentatively links cell wall glucan, wall thickness and consequent relative porosity to the sensitivity of Saccharomyces cerevisiae to chlorhexidine. 

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

IV. PARASITISM. Lysis by hydrolytic enzymes excreted by microorganisms is a well-known feature of mycoparasitism. Chitinase and P-l,3 glucanase (laminarase) are particularly important enzymes secreted by fungal mycoparasites capable of degrading the fungal cell wall components, chitin, and P-1,3 glucan (131-134). 

S. Bartnicki-Garcia and E. Lippman. Fungal cell wall composition. Handbook of Microbiology (A. L. Laskin and H. L. Lechvaluer, eds.). Chemical Rubber, Cleveland. Ohio. 1973, p. 229. 

Changes in cell-wall protein composition may regulate the molecular architecture of protein networks in a manner that allows new developmental outcomes for both fungal cell adhesion and root colonization. Further investigation of the structure and regulation of SRAP wall proteins will provide a more complete picture of their role in developing ectomycorrhizal tissues. Incompatibility between ectomycorrhizal hyphae and the host roots detected during the initial con-... 

F. Paris, J. Dexheimer, and F. Lapeyric, Cytochemical evidence of a fungal cell wall alteration during infection of Eucalyptus roots by the ectomycon hizal fungus Cenococcum geophUum. Arch Microbiol. 159 526 (1993). 

Amiri-Eliasi, B. Fenselau, C. Characterization of protein biomarkers desorbed by MALDI from whole fungal cells. Anal. Chem. 2001, 73, 5228-5231. 

---