Abstract: Candida spp. are common and aggressive pathogens. Because of the growing resistance of Candida spp. to current antifungals, novel targets, found in Candida spp. but not in humans or other flora, have to be identified. The alternative oxidase (AOX) is one such possibility. This enzyme is insensitive to cyanide, but is sensitive to compounds such as salicylhydroxamic acid (SHAM), disulfiram and n-alkyl gallates. The growth each of six Candida spp. was inhibited significantly by ~13 mM SHAM or 2 mM cyanide, albeit to differing extents. In C. dubliniensis, C. krusei and C. tropicalis the rate of O2 uptake was inhibited by 18-36% by 25 mM SHAM, but this had little or no effect on C. glabrata, C. guilliermondii or C. parapsilosis. Although SHAM substantially inhibited the growth of Candida spp., it is unlikely that the inhibition of AOX was the cause. Salicylhydroxamic acid is used therapeutically in the treatment of urinary tract infections and urolithiasis, but it also has some potential in the treatment of Candida spp. infection.
Abstract: The kinetic properties of enzymes are often reported
using the apparent KM and Vmax appropriate to the standard
Michaelis-Menten enzyme. However, this model is inappropriate to
enzymes that have more than one substrate or where the rate
expression does not apply for other reasons. Consequently, it is
desirable to have a means of estimating the appropriate kinetic
parameters from the apparent values of KM and Vmax reported for each
substrate. We provide a means of estimating the range within which
the parameters should lie and apply the method to data for glutamate
dehydrogenase from the nematode parasite of sheep Teladorsagia
circumcincta.
Abstract: Glomerular filtration rate (GFR) is a measure of
kidney function. It is usually estimated from serum concentrations of
cystatin C or creatinine although there has been considerable debate
in the literature about (i) the best equation to use and (ii) the
variability in the correlation between the concentrations of creatinine
and cystatin C. The equations for GFR can be written in a general
form and from these I calculate the error of the GFR estimates
associated with analyte measurement error. These show that the
error of the GFR estimates is such that it is not possible to distinguish
between the equations over much of the concentration range of either
analyte. The general forms of the equations are also used to derive
an expression for the concentration of cystatin C as a function of the
concentration of creatinine. This equation shows that these analyte
concentrations are not linearly related. Clinical reports of cystatin C
and creatinine concentration are consistent with the expression
derived.
Abstract: Candida spp. are common and aggressive pathogens.
Because of the growing resistance of Candida spp. to current
antifungals, novel targets, found in Candida spp. but not in humans
or other flora, have to be identified. The alternative oxidase (AOX)
is one such possibility. This enzyme is insensitive to cyanide, but is
sensitive to compounds such as salicylhydroxamic acid (SHAM),
disulfiram and n-alkyl gallates. The growth Candida albicans was
inhibited by SHAM (Ki = 9-15 mM) and cyanide (Ki = 2-4 mM),
albeit to differing extents. The rate of O2 uptake was inhibited by
less than 10% by 25 mM SHAM and by about 90% by 250 μM
KCN. Although SHAM substantially inhibited the growth of C.
albicans, it is unlikely that the inhibition of AOX was the cause.
Salicylhydroxamic acid is used therapeutically in the treatment of
urinary tract infections and urolithiasis, but it also has some potential
in the treatment of C. albicans infection.
Abstract: Fungal infections are becoming more common and the
range of susceptible individuals has expanded. While Candida
albicans remains the most common infective species, other Candida
spp. are becoming increasingly significant. In a range of large-scale
studies of candidaemia between 1999 and 2006, about 52% of 9717
cases involved C. albicans, about 30% involved either C. glabrata or
C. parapsilosis and less than 15% involved C. tropicalis, C. krusei or
C. guilliermondii. However, the probability of mortality within 30
days of infection with a particular species was at least 40% for C.
tropicalis, C. albicans, C. glabrata and C. krusei and only 22% for
C. parapsilopsis. Clinical isolates of Candida spp. grew at rates
ranging from 1.65 h-1 to 4.9 h-1. Three species (C. krusei, C. albicans
and C. glabrata) had relatively high growth rates (μm > 4 h-1), C.
tropicalis and C. dubliniensis grew moderately quickly (Ôëê 3 h-1) and
C. parapsilosis and C. guilliermondii grew slowly (< 2 h-1). Based
on these data, the log of the odds of mortality within 30 days of
diagnosis was linearly related to μm. From this the underlying
probability of mortality is 0.13 (95% CI: 0.10-0.17) and it increases
by about 0.09 ± 0.02 for each unit increase in μm. Given that the
overall crude mortality is about 0.36, the growth of Candida spp.
approximately doubles the rate, consistent with the results of larger
case-matched studies of candidaemia.
Abstract: Candida albicans ATCC 10231 had low endogenous activity of the alternative oxidase compared with that of C. albicans ATCC 10261. In C. albicans ATCC 10231 the endogenous activity declined as the cultures aged. Alternative oxidase activity could be induced in C. albicans ATCC 10231 by treatment with cyanide, but the induction of this activity required the presence of oxygen which could be replaced, at least in part, with high concentrations of potassium ferricyanide. We infer from this that the expression of the gene encoding the alternative oxidase is under the control of a redoxsensitive transcription factor.