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Salicylhydroxamic Acid Inhibits the Growth of Candida Albicans

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Salicylhydroxamic Acid Inhibits the Growth of Candida Albicans World Academy of Science, Engineering and Technology International Journal of Bioengineering and Life Sciences Vol:5, No:4, 2011 Salicylhydroxamic Acid Inhibits the Growth of Candida albicans Shu-Ying Marissa Pang, Stephen Tristram and Simon Brown chain enzyme that accepts electrons directly from ubiquinol Abstract—Candida spp. are common and aggressive pathogens. (UQH2) and reduces O2 to water. Because of the growing resistance of Candida spp. to current Alternative oxidase activity is inhibited by compounds such antifungals, novel targets, found in Candida spp. but not in humans as salicylhydroxamic acid (SHAM) [4], disulfiram and n-alkyl or other flora, have to be identified. The alternative oxidase (AOX) gallates [5, 6], none of which inhibit the activity of is one such possibility. This enzyme is insensitive to cyanide, but is sensitive to compounds such as salicylhydroxamic acid (SHAM), cytochrome oxidase. Conversely, cyanide inhibits disulfiram and n-alkyl gallates. The growth Candida albicans was cytochrome oxidase, but does not inhibit AOX. These two inhibited by SHAM (Ki = 9-15 mM) and cyanide (Ki = 2-4 mM), inhibitors can be used to distinguish between O2 uptake albeit to differing extents. The rate of O2 uptake was inhibited by catalysed by AOX and cytochrome oxidase. The disruption of less than 10% by 25 mM SHAM and by about 90% by 250 μM electron transfer by cyanide and SHAM would affect ATP KCN. Although SHAM substantially inhibited the growth of C. synthesis and the activity of metabolic pathways, either of albicans, it is unlikely that the inhibition of AOX was the cause. which would inhibit growth. Inhibition of AOX has been Salicylhydroxamic acid is used therapeutically in the treatment of urinary tract infections and urolithiasis, but it also has some potential reported to potentiate the inhibition of the growth of C. in the treatment of C. albicans infection. albicans by fluconazole [7]. It has been suggested that AOX is a viable target in the treatment of trypanosomes [8] and that Keywords—alternative oxidase, Candida albicans, growth, it plays an important role in the stress response in various respiration, salicylhydroxamic acid. fungi [9] and in plants [10]. Morover, hydroxamic acids (such as SHAM) inhibit the growth of some bacteria, some of which I. INTRODUCTION also have an AOX homologue [11], and other fungi [12, 13]. andida albicans is isolated from 15 – 60% of healthy Here, we report on the effects of SHAM and KCN on the C individuals. However, Candida spp. are increasingly growth of C. albicans in liquid culture and on plates, using a considered highly prevalent and aggressive pathogens because disk diffusion protocol [14]. We also report on the effect of of their growing resistance to the currently available SHAM and KCN on the rate of O2 uptake by C. albicans. antifungals. Several large-scale studies of candidaemia [1, 2] We show that both the growth of and O2 uptake by C. show that the probability of death within 30 days varied from albicans are inhibited by SHAM or KCN. However, about 40% for cases of infection with C. albicans, C. glabrata inhibition of AOX is not likely to be the cause of the effect of or C. tropicalis to about 20% with C. parapsilopsis. SHAM because the concentrations required (Ki) to inhibit Gudlaugsson et al. [3] concluded that the Candida spp. growth and O2 uptake differ considerably. Nevertheless, infections, rather than any underlying disease, accounted for SHAM has some potential in the treatment of C. albicans about 38% of deaths of patients with candidaemia. Although infection and is used in the treatment of urinary tract C. albicans and C. glabrata have been the most commonly infections and urolithiasis [15, 16]. isolated species, other species, such as C. tropicalis and C. krusei, are also associated with significant mortality [1, 2]. II. MATERIALS AND METHODS The growing antifungal resistance of Candida spp. and their pathogenicity necessitate the identification of novel potential A. Culture growth drug targets. Ideally, such targets should be found in Candida Candida albicans was obtained from the University of International Science Index, Bioengineering and Life Sciences Vol:5, No:4, 2011 waset.org/Publication/4710 spp., but not in humans or other flora. One such possibility is Tasmania culture collection and its identity was confirmed ® the alternative oxidase (AOX), which is an electron transfer using the Remel RapID™ Yeast Plus System (Remel Laboratories, Lenexa, Kansas, USA). S. -Y. M. Pang was with the School of Human Life Sciences, University of Candida albicans was grown in liquid YPD (1% (w/v) yeast Tasmania, Launceston, Tasmania 7250, Australia (e-mail: sympang@ extract, 2% (w/v) bacteriological peptone, 2% (w/v) glucose) utas.edu.au). S. Tristram is with the School of Human Life Sciences, University of in the presence or absence of either or both of KCN and Tasmania, Launceston, Tasmania 7250, Australia (e-mail: Stephen.Tristram@ SHAM. Routinely, cultures (50 mL YPD in a 250 mL conical utas.edu.au). flask) were inoculated with sufficient cells from an overnight S. Brown is with the School of Human Life Sciences, University of Tasmania, Launceston, Tasmania 7250, Australia (phone: +61-3-6324-5467; culture to get an initial A600 of 0.4 and grown for 15 h, unless fax: +61-3-6324-3995; e-mail: Simon.Brown@ utas.edu.au). otherwise specified, at (37 ± 1)°C in a shaking incubator (at International Scholarly and Scientific Research & Innovation 5(4) 2011 187 scholar.waset.org/1307-6892/4710 World Academy of Science, Engineering and Technology International Journal of Bioengineering and Life Sciences Vol:5, No:4, 2011 -1 200 min ). Where the cultures were monitored repeatedly, (= ln(Ac)) cell growth is not inhibited by the compound (so r = exit cultures on MacConkey agar (2% (w/v) peptone, 1% (w/v) r0), and no greater than the size of the plate (radius = R) on lactose, 0.5% (w/v) bile salts, 0.5% (w/v) NaCl, 0.0075% (w/v) which the cells are cultured. neutral red and 1.2% (w/v) agar), blood agar (5% (w/v) The direct application of (2) (the linear model) is only defibrinated horse blood and tryptone soya agar consisting of possible if growth is inhibited significantly over the range of 1.5% (w/v) tryptone, 0.5% (w/v) soya peptone, 0.5% (w/v) ln(A). Even then it requires that a decision be made about the NaCl and 1.5% (w/v) agar) and YPD agar (YPD supplemented location of the range in which the relationship is linear. with 1.5% (w/v) agar) plates were prepared to check for An extension of (2) (the bilinear model) involves an possible contamination. Candida spp. were maintained at objective estimation of ln(Ac) 37°C on YPD agar and subcultured onto a fresh plate every ⎧ 2 r0 , ln(A) ≤ ln(Ac ) three days. 2 ⎪ r = ⎨ 2 A (3) The Gompertz function [17], as parameterized by r + α ln( ), ln(A) > ln(A ) ⎪ 0 A c Zweitering et al. [18], but with the addition of a parameter to ⎩ c estimate the initial inoculum (A(0)) which makes use of all the obtained data and eliminates any A(t) = A(0) + []Amax − A(0) need to choose the linear data range. In (3), only α (which (1) has the same significance as in (2)) and the critical amount ⎪⎧ ⎡ μm exp(1) ⎤⎪⎫ ×exp⎨− exp⎢ ()λ − t +1⎥⎬ (Ac) have to be estimated by nonlinear regression, since r0 is A − A(0) ⎩⎪ ⎣ max ⎦⎭⎪ the actual radius of the disk. The bilinear model also requires was fitted directly to the growth data (A600) by nonlinear that growth is inhibited significantly over the range of ln(A). regression using the nlm function in R [19]. In (1), A(t) A third model (the logistic model) is based on the logistic represents the absorbance at 600 nm at time t (h), μm is the function and (2) -1 maximum growth rate (h ), λ is the lag time (h) and Amax is the 2 2 2 2(β − r0 ) maximum absorbance. Other models were tested, but the r = r0 + (4) ⎡ 2α ⎛ A ⎞⎤ improvement in the fit did not justify the introduction of any 1+ exp⎢− ln⎜ ⎟⎥ 2 ⎜ A ⎟ extra parameters (p = 0.187). ⎣⎢ β − r0 ⎝ 0 ⎠⎦⎥ B. Disk diffusion analysis where A0 is the inflection point of the logistic function, and α Disks (diameter = 6 mm) were prepared from Whatman’s has the same significance as in (2), and β is related to the antibiotic assay filter paper and autoclaved. Individual disks upper limit of the radius of the zone of clearing. This model were placed in the wells of a 96-well microtitre plate and facilitates the estimation of ln(Ac) even where there is only volumes of KCN or SHAM (in absolute ethanol) were added limited inhibition of growth. to each well to give 5 – 400 μmol KCN or 7.3 – 183 μmol C. Oxygen uptake measurements SHAM, respectively. The residual solvent was allowed to Cells were harvested after 15 h growth in liquid YPD by evaporate before the disks were used. centrifugation at 1335 × g for 15 min at 4°C (Sigma Diffusion assays were carried out on YPD plates to which Laboratory Centrifuge 4K15). The cells were washed with 50 was added 2.5 mL of a 0.5 McFarland standard suspension of mM Na2HPO4-NaH2PO4 (pH 6.5) and then resuspended to 5 Candida spp. prepared in 0.85% saline. The suspension was mL in the same buffer. The O2 uptake by cell suspensions allowed to distribute evenly across the plate and the excess was measured polarographically with a Clark-type O2 was discarded.
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