Section Review: Anti-infectives: Lipopeptide antifungal agents

Abstract

There is a need for safe and effective antifungal agents due to the rise in the immunocompromised patient population. Lipopeptides are an emerging class of antifungal agents. Two structural classes, the aureobasidins and echinocandins are discussed. The aureobasidins are cyclic lipodepsipeptides with an unknown mode of action. Although aureobasidin A possesses in vitro activity against Candida and Cryptococcus and is orally bioavailable, in vivo studies suggest that it is a Candida-only agent with the potential for activity against blastomycosis and histoplasmosis. Lipopeptides, represented by the echinocandin cyclic hexapeptides, are cidal agents which inhibit the synthesis of β-(1,3)-glucan. Fujisawa has disclosed FR901379, a lipopeptide that possesses intrinsic water solubility, suitable for parenteral administration, but is less potent than compounds disclosed by Lilly or Merck. Lilly has disclosed a phosphate ester prodrug, LY307853, with water solubility, usable oral bioavailability, potent Candida, Histoplasma, Aspergillus and Pneumocystis activities and good pharmacokinetics. The parent compound, LY303366, a pentyloxyterphenyl side chain derivative of echinocandin B, is reportedly identical to the phosphate in all aspects except aqueous solubility. Merck has disclosed a series of water soluble amine-bearing pneumocandin derivatives, L-705,589, L-731,373 and L-733,560, with good activity against Candida, Aspergillus and Pneumocystis. The combination analogue, L-733,560, shows good potency and primate pharmacokinetics.