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Influence of serum and albumin on echinocandin pharmacodynamicsNasar, Aasya Saira 08 November 2012 (has links)
Background: The use of human serum (HS) or bovine serum albumin (BSA) during
susceptibility testing may help discriminate between echinocandin susceptible and
resistant C. albicans and C. glabrata strains. However, the influence of these protein
components and that of specific FKS mutations on the in vitro potency of the
echinocandins remains unclear. Our objective was to evaluate the in vitro
pharmacodynamics of the echinocandins in the presence and absence of these biological
matrices against resistant C. albicans and C. glabrata isolates.
Methods: Thirteen C. albicans clinical isolates (2 wild-type and 11 FKS mutants (F641S
and S645P) and twenty C. glabrata clinical isolates (16 FKS mutants and 4 with
unknown resistance mechanisms) were used. MICs were measured in duplicate according
to the CLSI M27-A3 guideline for caspofungin, micafungin, and anidulafungin in RPMI,
or RPMI supplemented with either 5% HS or 5% BSA. Pharmacodynamic analysis was
also performed with the XTT viability assay, and non-linear regression analysis was usedto determine the IC50 values. Differences in geometric mean (GM) MICs and mean IC50
values were assessed by ANOVA and the Student’s t-test.
Results: The addition of BSA significantly increased the GM MIC (6-24 fold) and IC50
(9-25 fold) of each echinocandin compared to RPMI (p < 0.0001) for isolates with FKS
mutations. Increases in MIC (4-12 fold) and IC50 values (3-5 fold) were also observed
with the addition of HS. Although increases in MICs and IC50s were also observed
against the wild-type isolates, these values remained < 1 μg/mL for each echinocandin.
When comparing the results of specific FKS mutations in C. albicans, the MIC and IC50
values were higher in each growth condition for isolates with S645P mutations (HS &
BSA GM 8.0 & 12 μg/mL; mean IC50 5.5 & 21 μg/mL, respectively) compared to those
with F641S mutations (HS & BSA GM 3.7 & 9.8 μg/mL; IC50 4.0 & 16 μg/mL,
respectively).
Conclusions: The addition of HS and BSA significantly influenced the
pharmacodynamics of the echinocandins, but to different degrees. The specific FKS
mutation may influence these in vitro potency changes, but further work is needed to
evaluate these matrices and standardize echinocandin testing in their presence. / text
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THE ROLE OF SET1 MEDIATED HISTONE H3K4 METHYLATION IN ANTIFUNGAL DRUG RESISTANCE AND FUNGAL PATHOGENESIS IN CANDIDA SPECIESKortany M. Baker (13775098) 14 September 2022 (has links)
<p> </p>
<p>Fungal pathogens are an increasing threat to humans, plants, and animals worldwide. Death and disease caused by fungal pathogens results in the loss of over 1.5 million lives, 12 million tons of crops, and even entire species every year. <em>Candida </em>species are the leading cause of invasive fungal species lead by <em>Candida albicans, </em>and <em>Candida glabrata </em>in second. <em>Candida glabrata </em>intrinsically has a low susceptibility to azole treatment, and multidrug resistant isolates are becoming more common. Additionally, new emerging <em>Candida </em>species have been found, and most clinical isolates are resistant to one or more drugs. There is a critical need to better understand drug resistance and pathogenesis to generate new therapies. </p>
<p>Drug resistance can be caused by several different genetic factors, but until recently epigenetic factors have been frequently overlooked. Epigenetic research has revolutionized the treatment and detection of many cancers. And now, early research has shown epigenetic mechanisms play a role in drug resistance and pathogenesis in fungal species. Limited resources exist to combat fungal infections and understanding the epigenetic mechanisms that contribute to drug resistance and pathogenicity will provide new drug targets for future treatment.</p>
<p>Previous publications from the Briggs’ lab showed Set1-mediated histone H3K4 methylation was necessary for proper ergosterol homeostasis and Brefeldin A resistance. One of the three classes of antifungals, azoles, target the ergosterol pathway. The ergosterol connection resulted into this thesis project, investigating the role of Set1-mediated histone H3K4 methylation in drug resistance and pathogenicity in <em>Saccharomyces cerevisiae, Candida glabrata, Candida albicans, </em>and <em>Candida auris. </em>This research was the first to characterize the Set1 complex in <em>C. glabrata </em>and show it is the sole histone H3K4 methyltransferase in <em>C. glabrata </em>and <em>C. auris. </em>Additionally, it shows loss of <em>SET1 </em>in <em>C. glabrata </em>and <em>C. auris </em>reduces pathogenicity and alters drug efficacy. Interestingly, although the loss of <em>SET1</em> seems to cause a similar pathogenic defect in all three <em>Candida </em>species, the role Set1 plays in drug efficacy including which drug and severity varies amongst species and isolates. Altogether, this research project provides new possible drug targets for fungal treatment and knowledge added to the scientific community on the role of epigenetics in fungal pathogens. </p>
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