title: Increased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis.
abstract: The pneumocandins are natural lipopeptide products of the echinocandin class which inhibit the synthesis of 1,3-beta-D-glucan in susceptible 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 dehydration and reduction of the glutamine of pneumocandin B0 produced a semisynthetic compound (L-733,560) with intrinsic water solubility, significantly increased potency, and a broader antifungal spectrum. To evaluate the mechanism for the improved antifungal efficacy, we determined that L-733,560 was a more potent inhibitor of glucan synthase activity in vitro, did not affect the other membrane-bound enzymes tested, conferred susceptibility to lysis in the absence of osmotic support, and did not disrupt currents in liposomal bilayers or 86Rb+ fluxes from liposomes. In Aspergillus species L-733,560 also produced the same morphological alterations as pneumocandin B0. 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 synthesis and not by nonspecific membrane effects or a second mode of action.
authors.affiliation: Department of Infectious Disease Research, Merck Research Laboratories, Rahway, NJ 07065-0900.
authors.forename: M B
authors.initials: MB
authors.lastname: Kurtz
authors.forename: C
authors.initials: C
authors.lastname: Douglas
authors.forename: J
authors.initials: J
authors.lastname: Marrinan
authors.forename: K
authors.initials: K
authors.lastname: Nollstadt
authors.forename: J
authors.initials: J
authors.lastname: Onishi
authors.forename: S
authors.initials: S
authors.lastname: Dreikorn
authors.forename: J
authors.initials: J
authors.lastname: Milligan
authors.forename: S
authors.initials: S
authors.lastname: Mandala
authors.forename: J
authors.initials: J
authors.lastname: Thompson
authors.forename: J M
authors.initials: JM
authors.lastname: Balkovec
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D008051:Lipid Bilayers / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D010455:Peptides; D012414:Rubidium Radioisotopes / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; C089367:L 733560; D008051:Lipid Bilayers; D008081:Liposomes; D010455:Peptides; D012414:Rubidium Radioisotopes; D005964:Glucosyltransferases; C040232:glucan synthase