INCREASED ANTIFUNGAL ACTIVITY OF L-733,560, A WATER-SOLUBLE, SEMISYNTHETIC PNEUMOCANDIN, IS DUE TO ENHANCED INHIBITION OF CELL-WALL SYNTHESIS

The pneumocandins are natural lipopeptide products of the echinocandin class which inhibit the synthesis of 1,3-beta-D- glucan in susceptibl e fungi. The lack of a corresponding pathway in mammalian hosts makes this mode of action an attractive one for treating systemic infections . Substitution by an aminoethyl ether at the hemiaminal and dehydratio n and reduction of the glutamine of pneumocandin B-0 produced a semisy nthetic compound (L-733,560) with intrinsic water solubility, signific antly increased potency, and a broader antifungal spectrum. To evaluat e the mechanism for the improved antifungal efficacy, we determined th at L-733,560 was a more potent inhibitor of glucan synthase activity i n vitro, did not affect the other membrane-bound enzymes tested, confe rred susceptibility to lysis in the absence of osmotic support, and di d not disrupt currents in liposomal bilayers or Rb-86(+) fluxes from l iposomes. In Aspergillus species L-733,560 also produced the same morp hological alterations as pneumocandin B-0. A stereoisomer of L-733,560 with poor antifungal activity was a weak inhibitor of glucan synthase . All of these results support the notion that the enhanced antifungal activity of L-733,560 is achieved by superior inhibition of glucan sy nthesis and not by nonspecific membrane effects or a second mode of ac tion.