L-671,329, a new antifungal agent. III. In vitro activity, toxicity and efficacy in comparison to aculeacin.
L-671,329 is a novel, echinocandin-like natural product that possesses potent anti-Candida activity, including activity against Candida parapsilosis. The in vitro MICs of L-671,329 were comparable to aculeacin against 18 yeasts and three filamentous fungi in an agar dilution assay. L-671,329 lysed mouse red blood cells (RBCs) at a concentration of 400 micrograms/ml, but not at 50 or 12.5 micrograms/ml. Aculeacin lysed RBCs at 400 and 50 micrograms/ml. L-671,329 significantly prolonged survival of mice infected with Candida albicans (ED50 3.38 mg/kg) following twice-daily intraperitoneal dosing for five consecutive days. The prolongation observed was greater than that seen with aculeacin therapy (ED50 6.44 mg/kg). No acute or chronic toxicities of L-671,329 or aculeacin (as measured by mortality) were detected at a concentration of 100 mg/kg following intraperitoneal administration (TD50 greater than 100 mg/kg). Both L-671,329 and aculeacin eradicated cells of C. albicans from the kidneys of infected mice. L-671,329 eradicated the yeast at therapeutic concentrations of 12.5 to 100 mg/kg. Aculeacin eradicated yeast cells at therapy concentrations of 25 to 100 mg/kg. L-671,329 has potential as an anti-Candida compound.
Fromtling
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Department of Basic Microbiology, Merck Sharp & Dohme Research Laboratories, Rahway, N.J. 07065-0900.
Abruzzo
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D000818:Animals; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents / Q000494:pharmacology / Q000633:toxicity*; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D054714:Echinocandins; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D007668:Kidney / Q000382:microbiology; D008099:Liver / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D010455:Peptides; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000633:toxicity
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054714:Echinocandins; D010455:Peptides; D010456:Peptides, Cyclic; C058995:pneumocandin A(0); C011634:aculeacin A