High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against Candida albicans and Candida auris Biofilms
<p>Graphical representation of results from the initial screens for inhibitors of biofilm formation against <span class="html-italic">C. albicans</span> (<b>A</b>) and <span class="html-italic">C. auris</span> (<b>B</b>). The dotted lines indicate the 70% arbitrary threshold for initial hit identification.</p> "> Figure 2
<p>Evaluation of protective effects of treatment with ebselen (<b>A</b>), temsirolimus (<b>B</b>), and compound BAY 11-7082 (<b>C</b>) in the murine model of hematogenously disseminated infection by <span class="html-italic">C. albicans</span>.</p> "> Figure 3
<p>Evaluation of protective effects of treatment with ebselen (<b>A</b>) and temsirolimus <b>(B</b>) in the murine model of hematogenously disseminated infection by <span class="html-italic">C. auris</span>.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Strains, Cultivation Conditions, and Media
2.2. Chemical Library
2.3. High-Throughput Screen for Inhibitors of C. albicans and C. auris Biofilm Formation
2.4. Concentration-Dependent Assays for Confirmation of Initial Hits and Determination of Their Inhibitory Potency
2.5. Antifungal Susceptibility Testing to Determine the Spectrum of Activity of the Leading Repositionable Drugs Ebselen, Temsirolimus, and BAY 11-7082 against a Panel of Medically Important Fungi
2.6. Preliminary Examination of the In Vivo Antifungal Activity of the Leading Repositionable Compounds Ebselen, Temsirolimus, and BAY 11-7082 in Murine Models of Hematogenously Disseminated Candidiasis
3. Results and Discussion
3.1. High-Throughput Screening of the Drug Repurposing Hub for Inhibitors of C. albicans and C. auris Biofilm Formation
3.2. Concentration-Dependent Assays to Confirm “Hits” from the Initial Screen and Establish Their Potency
3.3. Determination of the Spectrum of Antifungal Activity of the Leading Repositionable Compounds Ebselen, Temsirolimus, and BAY 11-7082
3.4. In Vivo Efficacy of Ebselen, Temsirolimus, and BAY 11-7082 in the Murine Models of Hematogenously Disseminated Candidiasis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound Name | % Inhibition Initial Screen | Maximum % Inhibition from Dose–Response Assays | IC50 (µM) from Dose–Response Assays |
---|---|---|---|
Antifungals/Fungicides | |||
Anidulafungin | 92.32 | 99.18 | <0.078 |
Cerulenin | 98.27 | 96.08 | 4.625 |
Ciclopirox | 93.51 | 91.77 | 1.200 |
Flucytosine | 86.81 | 80.51 | 2.936 |
JIB04 | 74.9 | 76.2 | 21.220 |
Oligomycin-a | 73.23 | 72.00 | 5.131 |
Sertaconazole | 81.89 | 68.02 | 4.687 |
Sulconazole | 71.52 | 73.51 | 0.114 |
Terbinafine | 71.14 | 68.89 | 22.400 |
Terconazole | 69.58 | 69.37 | 1.304 |
Toyocamycin | 98.45 | 95.38 | 1.582 |
Voriconazole | 70.42 | 65.32 | <0.078 |
Antiseptics/Antibacterials | |||
Alexidine | 98.69 | 99.59 | 1.246 |
Benzethonium | 99.62 | 100 | 2.436 |
Benzyldimethylhexadecylammonium | 98.58 | 99.88 | 18.180 |
Bithionol | 84.19 | 81.24 | 7.344 |
Brilliant-green | 99.29 | 96.25 | 1.183 |
Cetrimonium | 99.01 | 99.59 | 4.759 |
Cetylpyridinium | 100.42 | 99.77 | 6.073 |
Chlorhexidine | 98.91 | 98.42 | 11.520 |
Chloroxine | 91.52 | 97.49 | 2.273 |
Clioquinol | 89.7 | 84.5 | 0.871 |
Crystal-violet | 98.65 | 96.47 | 1.346 |
Dequalinium | 98.15 | 96.47 | 15.440 |
Domiphen | 99.94 | 97.14 | 12.880 |
Octenidine | 97.93 | 95.02 | 9.014 |
Oritavancin | 81.94 | 83.87 | 15.460 |
Phenylmercuric acetate | 99.89 | 98.38 | <0.078 |
Thiomersal | 99.53 | 96.86 | 0.448 |
Triclosan | 98.65 | 98.48 | 6.220 |
Repositionable Compounds | |||
Anisomycin | 85.08 | 82.3 | 2.973 |
Atiprimod | 72.38 | 73.22 | 19.450 |
BAY 11-7082 | 99.67 | 98.01 | 6.733 |
BAY 11-7085 | 98.84 | 96.81 | 12.180 |
Broxaldine | 93.36 | 88.35 | 1.708 |
Ceritinib | 96.09 | 83.04 | 18.650 |
Clomifene | 79.4 | 100 | 9.279 |
Darapladib | 99.16 | 99.12 | 18.640 |
Enasidenib | 89.91 | 99.5 | 11.710 |
Fingolimod | 72.69 | 93.11 | 9.600 |
K145 | 96.85 | 96.43 | 18.420 |
NSC-319726 | 90.59 | 92.05 | 1.993 |
Otilonium | 97.28 | 97.43 | 6.750 |
Pinaverium | 76.42 | 75.02 | 25.970 |
Pitavastatin | 79.18 | 95.24 | 4.015 |
Plurisin-#1 | 74.23 | 70.88 | 27.760 |
Sanguinarium-chloride | 97.85 | 96.96 | 4.928 |
SC-144 | 77.72 | 84.39 | 9.163 |
Semapimod | 98.83 | 98.71 | 9.055 |
Sirolimus * | 80.96 | 88.30 | 0.606 |
Sirolimus * | 73.73 | 85.61 | 0.614 |
Temsirolimus | 71.54 | 84.43 | 0.376 |
Toremifene | 81.49 | 84.88 | 4.952 |
Triclabendazole | 70.53 | 62.4 | 15.740 |
U-18666A | 97.78 | 95.35 | 4.792 |
Compound Name | % Inhibition Initial Screen | Maximum % Inhibition from Dose–Response Assays | IC50 (µM) from Dose–Response Assays |
---|---|---|---|
Antifungals/Fungicides | |||
Anidulafungin | 77.09% | 95.08% | 3.621 |
Cerulenin | 82.94% | 87.71% | 30.640 |
Ciclopirox | 77.78% | 77.67% | 9.779 |
Flucytosine | 77.25% | 74.40% | 10.600 |
Ketoconazole | 76.00% | 57.90% | 10.720 |
Tavaborole | 91.78% | 96.11% | 1.075 |
Terconazole | 75.64% | 60.70% | 7.146 |
Antiseptics/Antibacterials | |||
Alexidine | 97.69% | 87.30% | 3.610 |
Benzethonium chloride | 104.00% | 89.55% | 8.898 |
Brilliant-green | 88.94% | 88.08% | 4.603 |
Cetylpyridinium | 100.19% | 81.16% | 17.060 |
Crystal-violet | 82.26% | 93.86% | 2.707 |
Cycloheximide | 73.54% | 86.69% | 2.574 |
Hexachlorophene | 81.50% | 95.90% | 4.989 |
Octenidine | 94.32% | 77.06% | 8.423 |
Phenylmercuric acetate | 102.10% | 95.49% | 0.210 |
Thiomersal | 92.70% | 92.83% | 0.541 |
Thonzonium | 101.31% | 91.40% | 8.406 |
Triclosan | 98.40% | 77.83% | 5.020 |
Repositionable Compounds | |||
BAY 11-7082 | 96.07% | 93.24% | 17.460 |
Bithionol | 89.07% | 74.40% | 5.367 |
Darapladib | 90.05% | 82.38% | 18.890 |
Ebselen | 95.21% | 82.59% | 16.910 |
KHK-IN-1 | 98.80% | 94.47% | 37.140 |
Plurisin-#1 | 81.30% | 73.37% | 38.860 |
Semapimod | 90.63% | 96.31% | 11.370 |
Temsirolimus | 98.62% | 91.40% | 0.965 |
Toremifene | 90.00% | 96.09% | 14.470 |
Tribomsalan | 69.57% | 62.93% | 25.560 |
Zotarolimus | 75.83% | 90.58% | 2.777 |
Species | Isolate | Ebselen | Temsirolimus | BAY 11-7082 | Fluconazole | |||
---|---|---|---|---|---|---|---|---|
50% | 100% | 50% | 100% | 50% | 100% | 50% | ||
C. parapsilosis QC | ATCC 22019 | 0.5 | 2 | 1 | 1 | 4 | 8 | 1 |
C. krusei QC | ATCC 6258 | 1 | 4 | 1 | 2 | 0.5 | 0.5 | 16 |
C. albicans | ATCC 90028 | 1 | 2 | 1 | 1 | 1 | 2 | 0.25 |
SC5314 | 2 | 2 | 1 | 1 | 1 | 2 | ≤0.125 | |
Ca-1 | 1 | 2 | 1 | 1 | 1 | 1 | 0.5 | |
C. auris | Cau-1 | 0.125 | 0.25 | 1 | 1 | 2 | 4 | >64 |
Cau-2 | 0.125 | 1 | 1 | 1 | 0.25 | 1 | >64 | |
Cau-3 | 0.25 | 0.25 | 1 | 1 | 2 | 4 | 2 | |
C. glabrata | Cg-1 | 1 | 2 | 0.5 | 1 | 1 | 2 | 64 |
Cg-2 | 1 | 2 | 0.5 | 1 | 1 | 2 | 4 | |
Cg-3 | 0.5 | 2 | 1 | 1 | 0.5 | 1 | 0.5 | |
C. parapsilosis | Cp-1 | 0.25 | 2 | 1 | 1 | 2 | 4 | 0.5 |
Cp-2 | 0.25 | 2 | 0.5 | 1 | 2 | 4 | 0.25 | |
Cp-3 | 0.5 | 2 | 1 | 1 | 2 | 4 | 0.5 | |
Cryptococcus neoformans | Cn-1 | 2 | 2 | 1 | >32 | 1 | 1 | 64 |
USC1597 | 2 | 4 | 1 | >32 | 1 | 1 | 4 | |
H99 | 2 | 2 | 1 | >32 | 1 | 1 | 16 |
Species | Isolate | Ebselen | Temsirolimus | BAY 11-7082 | Voriconazole | Posaconazole | |||
---|---|---|---|---|---|---|---|---|---|
50% | 100% | 50% | 100% | 50% | 100% | 100% | 100% | ||
P. variotii QC | MYA-3630 | 4 | 4 | 16 | >32 | 1 | 1 | 0.125 | ≤0.03 |
Rhizopus arrhizus | Rh-1 | 4 | >32 | >32 | >32 | 4 | 4 | - | 1 |
Rh-2 | 8 | >32 | >32 | >32 | 4 | 4 | - | 0.5 | |
Rh-3 | 2 | >32 | >32 | >32 | 0.5 | 1 | - | 0.5 | |
Mucor spp. | Mu-1 | 8 | >32 | >32 | >32 | 4 | 4 | - | 2 |
Mu-2 | 8 | >32 | >32 | >32 | 2 | 4 | - | 1 | |
Mu-3 | 4 | >32 | 0.125 | >32 | 2 | 4 | - | 2 | |
Aspergillus flavus | ATCC204304 | 4 | 4 | >32 | >32 | 4 | 4 | 1 | - |
Afl-1 | 4 | 4 | >32 | >32 | 2 | 4 | 1 | - | |
Afl-2 | 4 | 4 | >32 | >32 | 2 | 4 | 1 | - | |
Aspergillus fumigatus | AF293 | 4 | 4 | >32 | >32 | 1 | 1 | 0.5 | - |
Af-1 | 4 | 4 | >32 | >32 | 1 | 1 | >16 | - | |
Af-2 | 4 | 4 | >32 | >32 | 1 | 1 | 4 | - | |
Fusarium spp. | Fu-1 | 4 | 4 | 2 | >32 | 1 | 1 | >16 | - |
Fu-2 | 4 | 8 | 2 | >32 | 0.5 | 1 | >16 | - | |
Fu-3 | 4 | 8 | 1 | >32 | 1 | 2 | >16 | - | |
Lomentospora prolificans | Sc-1 | 4 | 8 | 0.5 | >32 | 0.5 | 0.5 | >16 | - |
Scedosporium spp. | Sc-2 | 4 | 4 | 1 | >32 | 0.5 | 0.5 | 2 | - |
Sc-3 | 2 | 2 | 0.5 | >32 | 0.25 | 0.5 | 1 | - | |
Altenaria | Al-1 | 0.5 | 2 | >32 | >32 | 0.5 | 1 | 1 | - |
Curvularia | Cu-1 | 1 | 2 | 16 | >32 | 0.5 | 1 | 0.5 | - |
Exserohilum | Ex-1 | 1 | 4 | 16 | >32 | 0.5 | 1 | 2 | - |
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Ajetunmobi, O.H.; Wall, G.; Vidal Bonifacio, B.; Martinez Delgado, L.A.; Chaturvedi, A.K.; Najvar, L.K.; Wormley, F.L., Jr.; Patterson, H.P.; Wiederhold, N.P.; Patterson, T.F.; et al. High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against Candida albicans and Candida auris Biofilms. J. Fungi 2023, 9, 879. https://doi.org/10.3390/jof9090879
Ajetunmobi OH, Wall G, Vidal Bonifacio B, Martinez Delgado LA, Chaturvedi AK, Najvar LK, Wormley FL Jr., Patterson HP, Wiederhold NP, Patterson TF, et al. High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against Candida albicans and Candida auris Biofilms. Journal of Fungi. 2023; 9(9):879. https://doi.org/10.3390/jof9090879
Chicago/Turabian StyleAjetunmobi, Olabayo H., Gina Wall, Bruna Vidal Bonifacio, Lucero A. Martinez Delgado, Ashok K. Chaturvedi, Laura K. Najvar, Floyd L. Wormley, Jr., Hoja P. Patterson, Nathan P. Wiederhold, Thomas F. Patterson, and et al. 2023. "High-Throughput Screening of the Repurposing Hub Library to Identify Drugs with Novel Inhibitory Activity against Candida albicans and Candida auris Biofilms" Journal of Fungi 9, no. 9: 879. https://doi.org/10.3390/jof9090879