title: Caspofungin inhibits Rhizopus oryzae 1,3-beta-D-glucan synthase, lowers burden in brain measured by quantitative PCR, and improves survival at a low but not a high dose during murine disseminated zygomycosis.
abstract: Rhizopus oryzae is the most common cause of zygomycosis, a life-threatening infection that usually occurs in patients with diabetic ketoacidosis. Despite standard therapy, the overall rate of mortality from zygomycosis remains >50%, and new strategies for treatment are urgently needed. The activities of caspofungin acetate (CAS) and other echinocandins (antifungal inhibitors of the synthesis of 1,3-beta-D-glucan synthase [GS]) against the agents of zygomycosis have remained relatively unexplored, especially in animal models of infection. We found that R. oryzae has both an FKS gene, which in other fungi encodes a subunit of the GS synthesis complex, and CAS-susceptible, membrane-associated GS activity. Low-dose but not high-dose CAS improved the survival of mice with diabetic ketoacidosis infected with a small inoculum but not a large inoculum of R. oryzae. Fungal burden, assessed by a novel quantitative PCR assay, correlated with increasing inocula and progression of disease, particularly later in the infection, when CFU counts did not. CAS decreased the brain burden of R. oryzae when it was given prophylactically but not when therapy was started after infection. These results indicate that CAS has significant but limited activity against R. oryzae in vivo and demonstrates an inverse dose-response effect. The potential for CAS to play a role in combination therapy against zygomycosis merits further investigation.
authors.affiliation: Division of Infectious Diseases, St. John's Cardiovascular Research Center, Los Angeles Biomedical Research Institute at Harbor-University of Californa, Los Angeles Medical Center, Torrance, CA 90502, USA. ibrahim@labiomed.org
authors.forename: Ashraf S
authors.initials: AS
authors.lastname: Ibrahim
authors.forename: Joel C
authors.initials: JC
authors.lastname: Bowman
authors.forename: Valentina
authors.initials: V
authors.lastname: Avanessian
authors.forename: Keturah
authors.initials: K
authors.lastname: Brown
authors.forename: Brad
authors.initials: B
authors.lastname: Spellberg
authors.forename: John E
authors.initials: JE
authors.lastname: Edwards
authors.forename: Cameron M
authors.initials: CM
authors.lastname: Douglas
mesh_terms: D000595:Amino Acid Sequence; D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D015139:Blotting, Southern; D001921:Brain / Q000382:microbiology* / Q000473:pathology; D000077336:Caspofungin; D015169:Colony Count, Microbial; D004271:DNA, Fungal / Q000235:genetics / Q000302:isolation & purification; D016883:Diabetic Ketoacidosis / Q000150:complications; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins; D005800:Genes, Fungal; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D055666:Lipopeptides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009091:Mucormycosis / Q000188:drug therapy* / Q000382:microbiology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012233:Rhizopus / Q000187:drug effects / Q000201:enzymology*; D013534:Survival; D020096:Zygomycosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality
chemical_list: D000935:Antifungal Agents; D004271:DNA, Fungal; D054714:Echinocandins; D055666:Lipopeptides; D010456:Peptides, Cyclic; D000666:Amphotericin B; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase; D000077336:Caspofungin