Antifungal agents: chemotherapeutic targets and immunologic strategies

Antifungal antibiotics

“…One reason for the slow progress compared to antibacterials is that, like mammalian cells, fungi are eukaryotes; and therefore agents that inhibit protein, RNA or DNA biosynthesis in fungi have greater potential for toxicity to the host as well (Georgopapadakou and Walsh 1994). The second reason is that, until recently, the incidence of life-threatening fungal infections was perceived as being too low to warrant aggressive research by the pharmaceutical companies (Georgopapadakou and Walsh 1996).…”

“…New targets actively pursued in the ergosterol biosynthesis pathway are oxidosqualene cyclase and v 24 methyl transferase. The latter has no mammalian counterpart (cholesterol is not methylated at C-24) and is thus a particularly attractive target (Oehlschlager and Czyzewska 1992;Georgopapadakou and Walsh 1996).…”

“…Sphingolipids are essential membrane components of both mammalian cells and fungi and are localized primarily on the outer leaflet of the fungal cytoplasmic membrane (Patton and Lester 1991;Mandala et al 1997;Mandala and Harris 2000). They have also been pursued as potential targets, as in the case of sphinofungins and folimycins (Georgopapadakou and Walsh 1996). The plasma membrane H + ATPase is an integral membrane protein belonging to the P-type class of ion-translocating ATPases and has been a target site for bafilomycins (Muroi et al 1993).…”

“…A key factor for its functions is its fluidity, which is determined by its lipid composition (Georgopapadakou and Walsh 1996;Wills et al 2000). Fungal sterols, which are structurally distinct from their mammalian counterparts, have been studied extensively in attempts to obtain novel antifungals (Weete 1989;Mercer 1993).…”

“…The plasma membrane H + ATPase is an integral membrane protein belonging to the P-type class of ion-translocating ATPases and has been a target site for bafilomycins (Muroi et al 1993). It is an abundant, essential enzyme involved in the maintenance of electrochemical proton gradients and the regulation of intracellular pH (Monk and Perlin 1994;Georgopapadakou and Walsh 1996).…”