The antifungal arsenal: alternative drugs and future targets

Abstract

Clinically available antifungals for the treatment of invasive fungal infections primarily target either ergosterol in the fungal cell membrane or 1,3-β-D-glucan in the fungal cell wall. These classes include the polyene amphotericin B, the triazoles, and the echinocandins. Although newer antifungals and improved formulations of others have advanced our ability to treat patients with invasive mycoses, these drugs are often limited by toxicities, drug interactions, and the need for intravenous administration. Several investigational agents are currently under development. These include those that also target either ergosterol or 1,3-β-D-glucan, but have advantages over currently available drugs. Among these are the tetrazoles VT-1129, VT-1161, and VT-1598 that are more specific for fungal Cyp51 and less so for mammalian CYP 450 enzymes, the echinocandin CD101 that has an extended half-life, and the glucan synthase inhibitor SCY-078, which is being developed for oral administration. In addition, several agents with novel mechanisms of action are also under development. These include the inositol acyltransferase AX001, the dihydroorotate dehydrogenase inhibitor F901318, and VL-2397, which is similar in structure to the siderophore ferrichrome. In addition to possibly overcoming the limitations of currently available antifungals, these newer agents may be less susceptible to mechanisms of resistance that may render antifungals ineffective. Each of these investigational agents has the potential to improve patient outcomes in the treatment of invasive mycoses.