Oceanapiside, a Marine Natural Product, Targets the Sphingolipid Pathway of Fluconazole-Resistant Candida glabrata

Oceanapiside (OPS), a marine natural product with a novel bifunctional sphingolipid structure, is fungicidal against fluconazole-resistant Candida glabrata at 10 μg/mL (15.4 μM). The fungicidal effect was observed at 3 to 4 h after exposure to cells. Cytological and morphological studies revealed that OPS affects the budding patterns of treated yeast cells with a significant increase in the number of cells with single small buds. In addition, this budding morphology was found to be sensitive in the presence of OPS. Moreover, the number of cells with single medium-sized buds and cells with single large buds were decreased significantly, indicating that fewer cells were transformed to these budding patterns, suggestive of inhibition of polarized growth. OPS was also observed to disrupt the organized actin assembly in C. glabrata, which correlates with inhibition of budding and polarized growth. It was also demonstrated that phytosphingosine (PHS) reversed the antifungal activity of oceanapiside. We quantified the amount of long chain-bases (LCBs) and phytoceramide from the crude extracts of treated cells using LC-ESI-MS. PHS concentration was elevated in extracts of cells treated with OPS when compared with cells treated with miconazole and amphotericin B. Elevated levels of PHS in OPS-treated cells confirms that OPS affects the pathway at a step downstream of PHS synthesis. These results also demonstrated that OPS has a mechanism of action different to those of miconazole and amphotericin B and interdicts fungal sphingolipid metabolism by specifically inhibiting the step converting PHS to phytoceramide.

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Posaconazole Activity against Candida glabrata after Exposure to Caspofungin or Amphotericin B

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01447-07 ◽

2007 ◽

Vol 52 (2) ◽

pp. 513-517 ◽

Cited By ~ 9

Author(s):

Elisabetta Spreghini ◽

Carmelo Massimo Maida ◽

Maria Eleonora Milici ◽

Giorgio Scalise ◽

Francesco Barchiesi

Keyword(s):

Cell Viability ◽

Amphotericin B ◽

Experimental Model ◽

Induction Therapy ◽

Candida Glabrata ◽

Sequential Therapy ◽

Yeast Cells ◽

Fungal Burden ◽

Therapeutic Advantage ◽

Broth Dilution

ABSTRACT We evaluated the effects of sequential therapy with caspofungin (CAS) or amphotericin B (AMB) followed by posaconazole (POS) against Candida glabrata. The susceptibilities to POS of yeast cells pre-exposed to CAS or AMB were identical to those of untreated cells as shown by standard Clinical and Laboratory Standards Institute broth dilution, cell viability, and disk diffusion methods. We then investigated the activity of sequential regimens in an experimental model of disseminated candidiasis. CAS given at 1 mg/kg/day for 2 days followed by POS at either 15 or 30 mg/kg/day significantly reduced the counts compared to the controls, but this treatment was not superior to the use of CAS alone. Also, sequential regimens with AMB given at 1 mg/kg/day for 2 days followed by POS (AMB/POS) were effective at reducing the fungal burden against the controls. In addition, AMB/POS with both doses of the triazole were significantly more effective than AMB alone. Overall, our data showed that there is no therapeutic advantage in using CAS followed by POS, whereas an induction therapy with AMB followed by a maintenance regimen with POS might be a suitable strategy in managing C. glabrata infections.

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Synthesis of leucascandrolide A

Pure and Applied Chemistry ◽

10.1351/pac200577071161 ◽

2005 ◽

Vol 77 (7) ◽

pp. 1161-1169 ◽

Cited By ~ 22

Author(s):

Ying Wang ◽

Jelena Janjic ◽

Sergey A. Kozmin

Keyword(s):

Growth Inhibition ◽

Natural Product ◽

Marine Natural Product ◽

Yeast Cells ◽

Leucascandrolide A ◽

Ring Systems ◽

Large Ring ◽

Stereocontrolled Synthesis ◽

Potent Growth

This paper describes a convergent and stereocontrolled synthesis of leucascandrolide A, a marine natural product that exhibits potent growth inhibition of mammalian and yeast cells. The approach features a substrate-directed relay of the stereochemical information via a series of highly diastereoselective transformations. Spontaneous macrolactolization discovered during this synthetic exercise has provided an unprecedented access to this marine macrolide and demonstrates a new tactic for assembling large-ring systems based on the thermodynamic preference of hemiacetalization.

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Amphotericin B- and Fluconazole-ResistantCandida spp., Aspergillus fumigatus, and Other Newly Emerging Pathogenic Fungi Are Susceptible to Basic Antifungal Peptides

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.3.702 ◽

1999 ◽

Vol 43 (3) ◽

pp. 702-704 ◽

Cited By ~ 94

Author(s):

Eva J. Helmerhorst ◽

Ingrid M. Reijnders ◽

Wim van ’t Hof ◽

Ina Simoons-Smit ◽

Enno C. I. Veerman ◽

...

Keyword(s):

Candida Albicans ◽

Aspergillus Fumigatus ◽

Amphotericin B ◽

Candida Glabrata ◽

Frog Skin ◽

Pathogenic Fungi ◽

Candida Krusei ◽

Histatin 5 ◽

Antifungal Peptides ◽

Fluconazole Resistant

ABSTRACT The present study shows that a number of basic antifungal peptides, including human salivary histatin 5, a designed histatin analog designated dhvar4, and a peptide from frog skin, PGLa, are active against amphotericin B-resistant Candida albicans,Candida krusei, and Aspergillus fumigatusstrains and against a fluconazole-resistant Candida glabrata isolate.

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