Antifungal lipopeptides: A tale of pseudomycin prodrugs and analogues

Abstract

Systemic fungal infections (SFI) can cause serious life-threatening diseases in normal healthy humans. Candida. aibicans, Cryptococcus neoformans and Aspergillus fumigatus are the major opportunistic pathogens responsiblefor SFI. The rising incidence of SFI, especially in immunocompromised patients, attests to the need for more effective therapies. Present treatment options are limited to three classes of compounds, the polyenes, the azoles and the recently approved lipopeptide caspofungin acetate. Amphotericin B and azole-based antdurigal agents have an inadequate spectrum of activity and rapid emergence of fungal resistance, limited dosage forms and a narrow therapeutic window. Several approaches have been taken to address these deficiencies, such as improving the biological and/or toxicology profiles of existing drugs or the search for novel antifungal lipopeptides. As a result of this search, several cyclic peptides endowed with promising antifungal activities have been identified, including aureobasidins, echinocandins, papulacandin B and the recently disclosed pseudomycins. one most significant progress on this front was the 2001 launch of caspolungin acetate in the U.S. for the parenteral treatment of invasive aspergillosis in patients refractory to or intolerant of other antifungal therapies. This review provides a brief update on a number of recently discovered antifungal lipopeptides, as well as structural modifications and evaluation of pseudomycin analogues and prodrugs.