Pneumocandins from Zalerion arboricola. IV. Biological evaluation of natural and semisynthetic pneumocandins for activity against Pneumocystis carinii and Candida species.
A series of lipopeptide compounds co-produced during the fermentation of pneumocandin A0 (L-671,329) and related semisynthetic compounds were evaluated in vivo against Pneumocystis carinii pneumonia and systemic candidiasis. In addition, they were tested in vitro against a panel of pathogenic Candida species and in a Candida membrane 1,3-beta-D-glucan synthesis assay. The results of these studies demonstrate that pneumocandin A0 and pneumocandin B0 (L-688,786) are the most potent compounds when considering both antipneumocystis and anticandida activity. Other compounds in the series are selectively more potent against P. carinii or Candida albicans suggesting a diverging structure-activity relationship. Evaluation of these compounds for their ability to inhibit C. albicans 1,3-beta-D-glucan synthesis in vitro demonstrates that they inhibit this process. A positive correlation between 1,3-beta-D-glucan synthesis inhibition and in vitro antifungal activity was also demonstrated for some of the pneumocandins.
Schmatz
D M
DM
Merck Research Laboratories, Rahway, N.J. 07065.
Abruzzo
G
G
Powles
M A
MA
McFadden
D C
DC
Balkovec
J M
JM
Black
R M
RM
Nollstadt
K
K
Bartizal
K
K
D000818:Animals; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects; D004195:Disease Models, Animal; D054714:Echinocandins; D004912:Erythrocytes / Q000187:drug effects; D005936:Glucans / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D003904:Mitosporic Fungi / Q000737:chemistry*; D010455:Peptides; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology; D011010:Pneumocystis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D047071:beta-Glucans
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054714:Echinocandins; D005936:Glucans; D010455:Peptides; D010456:Peptides, Cyclic; D047071:beta-Glucans; C058995:pneumocandin A(0); C079465:pneumocandin B(0); C033363:beta-1,3-glucan