Effect of antimycotic agents on the activity of aspartyl proteinases secreted by Candida albicans

Abstract

The inhibitory effect of human immunodeficiency virus (HIV) proteinase inhibitors amprenavir and saquinavir and antifungal agents terbinafine, ketoconazole, amphotericin B and ciclopiroxolamine on aspartyl proteinases (Saps) secreted by Candida albicans was tested in an in vitro spectophotometric assay. As expected, both HIV proteinase inhibitors showed a significant inhibitory effect on Sap activity, which was comparable to that of the classical aspartyl proteinase inhibitor pepstatin A (P < 0.001). Antifungal drugs such as ketoconazole, terbinafine and amphotericin B had no, or only minor, inhibitory effects on proteolytic activity. In contrast, a significant reduction in Sap activity could be demonstrated during treatment with the antifungal agent ciclopiroxolamine (P < 0.001). These results point to a multiple effect of this antimycotic agent and might explain the reduced adherence of C. albicans to human epithelial cells at subinhibitory doses.

1-Alkyl-(N,N-dimethylamino)pyridinium bromides: inhibitory effect on virulence factors of Candida albicans and on the growth of bacterial pathogens

“…Maximum activity was observed in control cells without treatment with any inhibitor. Cells treated with pepstatin A, a known proteinase inhibitor, showed decreased levels of Candida albicans proteinase activity, with~72 % of Sap production inhibited, in agreement with the results of a previous study (Schaller et al, 2003). The assay was also performed with the standard antifungal agent amphotericin B (at 5 and 10 mg ml 21 ); there was no significant reduction in proteinase activity at the concentration of 5 mg ml…”

Virulence of Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis in reconstituted human tissue models

“…Ebelactone B protected the oral epithelial tissue from the disruptive effects of the C. parapsilosis. Since secreted aspartic proteinases are important virulence factors in C. albicans infections and inhibition of these proteinases have a protective effect for the host (De Bernardis et al, 2001;Hube and Naglik, 2001;Schaller et al, 2003), we used Pepstatin A to examine the effect of inhibiting proteinase during C. parapsilosis infection and found that the compound protected against the disruptive effects of fungus on RHT. The reduction in damage to RHT by Ebelactone B and Pepstatin A indicate that lipases and aspartic proteinases are involved in the pathogenesis of C. parapsilosis disease.…”

“…Secreted aspartic proteinases have been reported as important pathogenic factors for C. albicans infections (Naglik et al, 2004). Pepstatin A, a specific aspartic proteinase inhibitor, has been shown to inhibit the initial penetration of C. albicans through different mucosal surfaces and reduce histopathological alterations during experimental cutaneous candidiasis in different in vitro models (Schaller et al, 2003). Given the rising importance of C. parapsilosis in our patients, there is an urgent need for models that enable the study of interactions of this fungus with human tissues.…”

Candida parapsilosis, an Emerging Fungal Pathogen

“…Another group found that ritonavir reduced Sap activity but that saquinavir did not (11). Pepstatin A, a specific aspartic proteinase inhibitor, blocks the initial penetration of C. albicans and C. parapsilosis through mucosal surfaces and reduces histopathological alterations during experimental cutaneous candidiasis (95,249). Hence, Saps are a potential target for drug development.…”