Affiliation:
1. Department of Microbiology and Immunology, Georgetown University,1 and
2. Amulet Pharmaceuticals Inc.,2 Washington, D.C. 20007
Abstract
ABSTRACT
The candidacidal activity of nitric oxide (NO) as delivered by a class of compounds termed diazeniumdiolates has been investigated. Diazeniumdiolates are stable agents capable of releasing NO in a biologically usable form at a predicted rate, and three such compounds were examined for activity. One compound, (
Z
)-1-[
N
-(2-aminoethyl)-
N
-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), proved to be most suitable for examining NO activity due to its relatively long half-life (20 h) and because of limited candidacidal activity of the uncomplexed DETA nucleophile. DETA-NO was active against six species of
Candida
for which the MICs necessary to inhibit 50% growth (MIC
50
s) ranged from 0.25 to 1.0 mg/ml.
C. parapsilosis
and
C. krusei
were the most susceptible to the compound. In addition to a determination of NO effects alone, the complex was utilized to investigate the synergistic potential of released NO in combination with ketoconazole, fluconazole, and miconazole. Activity was investigated in vitro against representative strains of
Candida albicans
,
C. krusei
,
C. parapsilosis
,
C. tropicalis
,
C. glabrata
, and
C. dubliniensis
. Determination of MIC
50
, MIC
80
and MICs indicated that DETA-NO inhibits all strains tested, with strains of
C. parapsilosis
and
C. krusei
being consistently the most sensitive. The combination of DETA-NO with each azole was synergistic against all strains tested as measured by fractional inhibitory concentration indices that ranged from 0.1222 to 0.4583. The data suggest that DETA-NO or compounds with similar properties may be useful in the development of new therapeutic strategies for treatment of
Candida
infections.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
34 articles.
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