title: In vitro antifungal activities and in vivo efficacies of 1,3-beta-D-glucan synthesis inhibitors L-671,329, L-646,991, tetrahydroechinocandin B, and L-687,781, a papulacandin.
abstract: The in vivo anti-Candida activities of 1,3-beta-D-glucan synthesis inhibitors L-671,329, L-646,991 (cilofungin), L-687,901 (tetrahydroechinocandin B), and L-687,781 (a papulacandin analog) were evaluated by utilizing a murine model of disseminated candidiasis that has enhanced susceptibility to Candida albicans but increased sensitivity for discriminating antifungal efficacy. DBA/2 mice were challenged intravenously with 1 x 10(4) to 5 x 10(4) CFU of C. albicans MY1055 per mouse. Compounds were administered intraperitoneally at concentrations ranging from 1.25 to 10 mg/kg of body weight twice daily for 4 days. At 6 h and 1, 2, 3, 4, 7, and 9 days after challenge, five mice per group were sacrificed and their kidneys were homogenized and plated for enumeration of Candida organisms (CFU per gram). Progressiveness of response trends and no-statistical-significance-of-trend doses were derived to rank compound efficacy. 1,3-beta-D-Glucan synthesis 50% inhibitory concentrations were determined by using a C. albicans (MY1208) membrane glucan assay. Candida and Cryptococcus neoformans MICs and minimal fungicidal concentrations were determined by broth microdilution. L-671,329, L-646,991, L-687,901, and L-687,781 showed similar 1,3-beta-D-glucan activities, with 50% inhibitory concentrations of 0.64, 1.30, 0.85, and 0.16 micrograms/ml, respectively. Data from in vitro antifungal susceptibility studies showed that L-671,329, L-646,991, and L-687,901 had similar MICs ranging from 0.5 to 1.0 micrograms/ml, while L-687,781 showed slightly higher MICs of 1.0 to 2.0 micrograms/ml for C. albicans MY1055. Lipopeptide compounds were ineffective against C. neoformans strains. Results from in vivo experiments comparing significant trend and progressiveness in response analyses indicated that L-671,329 and L-646,991 were equipotent but slightly less active than L-687-901, while L-687,781 was ineffective at 10 mg/kg. Fungicidal activities of L-671,329, L-646,991, and L-687,901 were observed in vivo, with significant reduction in Candida CFU per gram of kidneys compared with those in sham-treated mice at doses of > or = 2.5 mg/kg evident as early as 1 day after challenge.
authors.affiliation: Merck & Co., Inc., Rahway, New Jersey 07065.
authors.forename: K
authors.initials: K
authors.lastname: Bartizal
authors.forename: G
authors.initials: G
authors.lastname: Abruzzo
authors.forename: C
authors.initials: C
authors.lastname: Trainor
authors.forename: D
authors.initials: D
authors.lastname: Krupa
authors.forename: K
authors.initials: K
authors.lastname: Nollstadt
authors.forename: D
authors.initials: D
authors.lastname: Schmatz
authors.forename: R
authors.initials: R
authors.lastname: Schwartz
authors.forename: M
authors.initials: M
authors.lastname: Hammond
authors.forename: J
authors.initials: J
authors.lastname: Balkovec
authors.forename: F
authors.initials: F
authors.lastname: Vanmiddlesworth
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001393:Azoles / Q000627:therapeutic use; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology; D054714:Echinocandins; D005936:Glucans / Q000096:biosynthesis*; D007668:Kidney / Q000382:microbiology; D007928:Lethal Dose 50; D051379:Mice; D008811:Mice, Inbred DBA; D008826:Microbial Sensitivity Tests; D010455:Peptides; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use; D011714:Pyrans / Q000494:pharmacology / Q000627:therapeutic use; D047071:beta-Glucans
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001393:Azoles; D054714:Echinocandins; D005936:Glucans; D010455:Peptides; D010456:Peptides, Cyclic; D011714:Pyrans; D047071:beta-Glucans; C058995:pneumocandin A(0); C065110:L 687781; C077148:tetrahydroechinocandin B; C042101:cilofungin; C033363:beta-1,3-glucan