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. 1999 Feb;43(2):233-9.
doi: 10.1128/AAC.43.2.233.

Amphotericin B and fluconazole affect cellular charge, macrophage phagocytosis, and cellular morphology of Cryptococcus neoformans at subinhibitory concentrations

J D Nosanchuk  1 , W Cleare, S P Franzot, A Casadevall
Affiliations

Amphotericin B and fluconazole affect cellular charge, macrophage phagocytosis, and cellular morphology of Cryptococcus neoformans at subinhibitory concentrations

J D Nosanchuk et al. Antimicrob Agents Chemother. 1999 Feb.

Abstract

Amphotericin B (AmB) and fluconazole (FLU) are the major antifungal drugs used in the treatment of cryptococcosis. Both drugs are believed to exert their antifungal effects through actions on cell membrane sterols. In this study we investigated whether AmB and FLU had other, more subtle effects on C. neoformans that could contribute to their therapeutic efficacy. C. neoformans cells were grown in media with subinhibitory concentrations of either AmB or FLU and analyzed for cellular charge, phagocytosis by macrophages with antibody and complement opsonins, appearance by scanning electron and light microscopies, and release of the capsular polysaccharide glucuronoxylomannan into the culture medium. Growth in the presence of either AmB or FLU resulted in major reductions in cellular charge, as measured by determination of the zeta potential. Phagocytosis studies demonstrated that exposure of C. neoformans to subinhibitory concentrations of AmB or FLU enhanced phagocytosis by macrophages. Scanning electron microscopy revealed that a large proportion of cells had an altered capsular appearance. Cells grown in medium with either AmB or FLU were smaller and released more glucuronoxylomannan into the culture medium than cells grown without antibiotics. The results suggest additional mechanisms of action for AmB and FLU that may be operative in body compartments where drug levels do not achieve the MICs. Furthermore, the results suggest mechanisms by which AmB and FLU can cooperate with humoral and cellular immune defense systems in controlling C. neoformans infections.

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Figures

FIG. 1
FIG. 1
Phagocytic index (number of organisms engulfed divided by number of macrophages) for strains of C. neoformans grown with or without antifungal agents. MAb, MAb 18B7; comp, complement from 20% FCS (not heat inactivated). Each bar represents the results for three wells. ∗, P ≤ 0.001 for comparison of the results for either AmB- or FLU-treated cells with those for the PBS control for each group of experiments.
FIG. 2
FIG. 2
C. neoformans cells grown in the presence of subinhibitory concentrations of AmB or FLU vary morphologically. Encapsulated cryptococcal cells of strain ATCC 24076 grown in medium with 0.5 the MIC of AmB can appear normal (A) or have shed part or all of their capsules (B and C, respectively). Acapsular strain CAP67 typically appears in the shape of a lemon (D) but more commonly appears round when it is grown with 0.5 the MIC of AmB or FLU (E). Magnifications, ×2,000.
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