Affiliation:
1. Glaxo Wellcome S.A., 28760 Tres Cantos, Madrid, Spain,1 and
2. Glaxo Wellcome SpA, 37100 Verona, Italy2
Abstract
ABSTRACT
GM 193663, GM 211676, GM 222712, and GM 237354 are new semisynthetic derivatives of the sordarin class. The in vitro antifungal activities of GM 193663, GM 211676, GM 222712, and GM 237354 against 111 clinical yeast isolates of
Candida albicans
,
Candida kefyr
,
Candida glabrata
,
Candida parapsilosis
,
Candida krusei
, and
Cryptococcus neoformans
were compared. The in vitro activities of some of these compounds against
Pneumocystis carinii
, 20 isolates each of
Aspergillus fumigatus
and
Aspergillus flavus
, and 30 isolates of emerging less-common mold pathogens and dermatophytes were also compared. The MICs of GM 193663, GM 211676, GM 222712, and GM 237354 at which 90% of the isolates were inhibited (MIC
90
s) were 0.03, 0.03, 0.004, and 0.015 μg/ml, respectively, for
C. albicans
, including strains with decreased susceptibility to fluconazole; 0.5, 0.5, 0.06, and 0.12 μg/ml, respectively, for
C. tropicalis
; and 0.004, 0.015, 0.008, and 0.03 μg/ml, respectively, for
C. kefyr
. GM 222712 and GM 237354 were the most active compounds against
C. glabrata
,
C. parapsilosis
, and
Cryptococcus neoformans
. Against
C. glabrata
and
C. parapsilosis
, the MIC
90
s of GM 222712 and GM 237354 were 0.5 and 4 μg/ml and 1 and 16 μg/ml, respectively. The MIC
90
s of GM 222712 and GM 237354 against
Cryptococcus neoformans
were 0.5 and 0.25 μg/ml, respectively. GM 193663, GM 211676, GM 222712, and GM 237354 were extremely active against
P. carinii
. The efficacies of sordarin derivatives against this organism were determined by measuring the inhibition of the uptake and incorporation of radiolabelled methionine into newly synthesized proteins. All compounds tested showed 50% inhibitory concentrations of <0.008 μg/ml. Against
A. flavus
and
A. fumigatus
, the MIC
90
s of GM 222712 and GM 237354 were 1 and 32 μg/ml and 32 and >64 μg/ml, respectively. In addition, GM 237354 was tested against the most important emerging fungal pathogens which affect immunocompromised patients.
Cladosporium carrioni
,
Pseudallescheria boydii
, and the yeast-like fungi
Blastoschizomyces capitatus
and
Geotrichum clavatum
were the most susceptible of the fungi to GM 237354, with MICs ranging from ≤0.25 to 2 μg/ml. The MICs of GM 237354 against
Trichosporon beigelii
and the zygomycetes
Absidia corymbifera
,
Cunninghamella bertholletiae
, and
Rhizopus arrhizus
ranged from ≤0.25 to 8 μg/ml. Against dermatophytes, GM 237354 MICs were ≥2 μg/ml. In summary, we concluded that some sordarin derivatives, such as GM 222712 and GM 237354, showed excellent in vitro activities against a wide range of pathogenic fungi, including
Candida
spp.,
Cryptococcus neoformans
,
P. carinii
, and some filamentous fungi and emerging invasive fungal pathogens.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
79 articles.
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