In vitro and in vivo anticandidal activity of human immunodeficiency virus protease inhibitors.
Highly active antiretroviral therapy that includes human immunodeficiency virus (HIV) aspartyl protease inhibitors (PIs) causes a decline in the incidence of some opportunistic infections in AIDS, and this decline is currently attributed to the restoration of specific immunity. The effect of two PIs (indinavir and ritonavir) on the enzymatic activity of a secretory aspartyl protease (Sap) of Candida albicans (a major agent of mucosal disease in HIV-infected subjects) and on growth and experimental pathogenicity of this fungus was evaluated. Both PIs strongly (>/=90%) and dose dependently (0.1-10 microM) inhibited Sap activity and production. They also significantly reduced Candida growth in a nitrogen-limited, Sap expression-dependent growth medium and exerted a therapeutic effect in an experimental model of vaginal candidiasis, with an efficacy comparable to that of fluconazole. Thus, besides the expected immunorestoration, patients receiving PI therapy may benefit from a direct anticandidal activity of these drugs.
Department of Bacteriology and Medical Mycology, Istituto Superiore di Sanità, 00161 Rome, Italy. cassone@iss.it
A
A
Cassone
F
F
De Bernardis
A
A
Torosantucci
E
E
Tacconelli
M
M
Tumbarello
R
R
Cauda
D017088:AIDS-Related Opportunistic Infections / Q000382:microbiology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development / Q000302:isolation & purification; D002180:Candidiasis, Oral / Q000382:microbiology; D002181:Candidiasis, Vulvovaginal / Q000188:drug therapy* / Q000382:microbiology; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019469:Indinavir / Q000494:pharmacology* / Q000627:therapeutic use; D010436:Pepstatins / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use; D051381:Rats; D019438:Ritonavir / Q000494:pharmacology* / Q000627:therapeutic use
D000935:Antifungal Agents; D017320:HIV Protease Inhibitors; D010436:Pepstatins; D011480:Protease Inhibitors; C014195:Streptomyces pepsin inhibitor; D019469:Indinavir; D016282:Aspartic Acid Endopeptidases; D019438:Ritonavir; C031375:pepstatin