Quick viewing(Text Mode)

Table S1. Characteristics of Repurposed Drugs/Compounds for Control of Fungal Pathogens. 1 Compounds Original Functions Target F

Table S1. Characteristics of Repurposed Drugs/Compounds for Control of Fungal Pathogens. 1 Compounds Original Functions Target F

Table S1. Characteristics of repurposed drugs/compounds for control of fungal pathogens. 1

Repurposing methods; Compounds Original functions Target fungi References cellular processes affected A. IN SILICO,

COMPUTATIONAL Computational chemogenomics; Vistusertib, Anti-neoplastic drug Paracoccidioides species fungal phosphatidylinositol 3-kinase [15] BGT-226 candidates (TOR2) , , , Candida dubliniensis, Candida parapsilosis, fumigatus, Aspergillus flavus, oryzae, Rhizopus microspores, Rhizomucor pusillus, Computational, Docking fluvastatin Rhizomucor miehei, racemosus, with cytochrome P450 (CYP51) Fluvastatin Anti-high & [18,19] Mucor mucedo, Mucor circinelloides, model; triglycerides (blood) Absidia corymbifera, Absidia glauca, inhibition of growth and biofilm mentagrophytes, formation , , Microsporum gypseum, Paecilomyces variotii, Syncephalastrum racemosum, Pythium insidiosum Ligand-based virtual screening, C. albicans, C. parapsilosis, Plant chorismate mutase homology modelling, molecular [16] Abscisic acid Aspergillus niger, inhibitor docking; T. rubrum, Trichophyton mentagrophytes chorismate mutase Homology modeling and molecular docking; P. insidiosum, Candida species, putative aldehyde dehydrogenase Disulfiram Treatment of alcoholism Cryptococcus species, A. fumigatus, [17,22] and urease activities, bind/inactivate multiple proteins of P. insidiosum Raltegravir (MDDR, In silico ligand-based, molecular DrugBank, Antiviral drug Paracoccidioides species docking, murine assay; [20] TargetMol thioredoxin reductase databases)

1 Killing kinetics assay, post- Anti-depression drug effect; in silico docking; [21] inhibit biosynthesis B. EXPERIMENTAL,

DRUG SYNERGISM Candida species, Cryptococcus species, , Saccharomyces cerevisiae, 2 CLSI; gene-drug network tamoxifen, Psychiatric , Lomentospora prolificans, interactions analysis; clomiphene, estrogen modulator, Curvularia lunata, Curvularia geniculata, species- or genus-specific synergism sertraline, , anti-platelet Curvularia spicifera, Alternaria alternata, with FLU, VOR, CAS or AMB; suloctidil, [23,24,29] aggregation, serine incarnatum, Fusarium solani, perturbed membrane permeability L-cycloserine palmitoyl-transferase Fusarium verticillioides, Scedosporium boydii, or inhibited sphingolipid (Prestwick inhibitor Scedosporium apiospermum, biosynthesis Chemical Library) Purpureocillium lilacinum,

Paecilomyces variottii, asahii C. auris, seven Candida species, CLSI M27-A3, P. variotii, , Ebselen Anti-cardiovascular disease, synergism with FLU (C. albicans), Rhizopus arrhizus, A. fumigatus, (Prestwick arthritis, stroke, VOR (Fusarium species) or AMB [25-28] A. niger, Fusarium oxysporum, Chemical Library) atherosclerosis, cancer, etc. (Trichosporon asahii) F. solani, S. apiospermum,

Lomentospora prolificans, T. asahii 3 EUCAST, synergism with VOR, Suloctidil, ITR, POS, MICO or ; Anti-cardiovascular disease, interaction with the plasma pamoate, arthritis, stroke, C. albicans, C. auris, membrane H+-ATPase, Ebselen atherosclerosis, cancer, etc., Exophiala dermatitidis [15,30,31,33,34] inhibition of membrane (Prestwick antiplatelet, trafficking, vacuolar biogenesis, Chemical Library) drugs biofilm inhibition & resistance

management Bromperidol C. albicans, C. glabrata, Checkerboard bioassay, Antipsychotic drugs [32] derivatives Aspergillus terreus synergism with High throughput synergistic screen Review: (HTSS) platform, Anti-virulence CLSI M38-A2; agents; resistance [39] Anti-virulence factors C. albicans targeting virulence factors (e.g., management, environmental adaptation factors, antifungal adhesins, morphogenesis, secreted repurposing enzymes, phenotype switching,

2 biofilms), antifungal synergistic drug combination database (ASDCD) (Candida, Cryptococcus, Rhodotorula, Time-kill study, pachydermatis, checkerboard assay; Exophiala dermatitidis synergism with polyenes & azoles, S. cerevisiae), Polymyxin B, colistin synergism with CAS, (Aspergillus, Fusarium, [35-38,40-44] colistin polymyxin B: overcoming multidrug Scedosporium, Lichtheimia, Rhizopus, resistance, Geosmithia argillacea, synergism with Zwiebelane A in Zygomycetes), fungal vacuole disruption) Batrachochytrium salamandrivorans CLSI M27-A3; calmodulin inhibition, structural C. neoformans, C. albicans, scaffolds Tamoxifen Estrogen Schizosaccharomyces pombe (alkylamino group, aliphatic [46-48] substituent, electronegative substituents), synergism with AMB CLSI M27-A3, C. neoformans gene deletion library assay, macrophage assay, synergism Tamoxifen, Estrogen receptor antagonists C. neoformans with FLU; [49] Toremifene prevent calmodulin binding to calcineurin (Cna1), block Cna1 activation C. albicans, C. glabrata, Candida tropicalis, , Candida parapsilosis Candida utilis, S. cerevisiae, R. oryzae, T. mentagrophytes, T. rubrum, M. canis, M. gypseum, CLSI M-27A, A. flavus, A. fumigatus, A. terreus, synergism with ITR or AMB; Lovastatin Anti-cholesterol drug [45,50-59] A. niger, Paecilomyces variotii, inhibit ergosterol biosynthesis, , Rhizopus homothallicus, planktonic cells and biofilms Mucor circinelloides, Mucor racemosus, Cunninghamella bertholletiae, Mortierella wolfii, Syncephalastrum racemosu,

3 Mycotypha africana EUCAST, macrophage test, C. neoformans, Cryptococcus gattii, antibiofilm, synergism of C. albicans, C. glabrata, C. krusei with FLU, ITR, ISA, C. parapsilosis, C. tropicalis, Anti-inflammatory drug, VOR, POS, CAS or AMB; , Ibuprofen Candida guilliermondii, T. asahii, [60-64,67,69,70] blood thinners activation of the high-osmolarity Trichophyton mentagrophytes, pathway, reactive oxygen , species-mediated membrane M. circinelloides damage Drospirenon, , Biofilm cell titer blue assay, Anti-anginal, Birth control, Toremifene C. albicans, C. glabrata checkerboard bioassay, [68] Estrogen receptor modulator (Pharmakon1600 synergism with AMB or CAS library) , , , Chenodiol, C. neoformans, Candida species , Antibacterial drug, EUCAST-AFST E.DEF 7.3, (including C. utilis, C. krusei, C. glabrata) , Treatment of high blood synergism with AMB; [66,71,72,74] Pythium insidiosum, , pressure, , etc. anti-hyphal and biofilm activity Mycosphaerella graminicola Cloperastine, (Prestwick Chemical Library) Susceptibility testing, synergism with the calcineurin inhibitor FK506; Eltrombopag calcineurin pathway, (Compound lipid biosynthesis, Thrombopoietin receptor C. neoformans, C. gattii, [73] library of 1018 membrane component, C. glabrata, T. rubrum FDA-approved transporter genes, drugs) capsule & biofilm formation, melanin production, growth ability at 37°C Thirty-one C. neoformans, Fusarium culmorum, CLSI M27-A2, murine phagocyte Anti-psychotic, Anti- drugs/molecules; Fusarium falciforme, Fusarium nelsonii, assay, synergism with FLU, VOR, depressant, [75,80] , F. oxysporum, F. solani, CAS or AMB; Anti-estrogen, etc. F. verticillioides calmodulin inhibition

4 (Prestwick Chemical Library) XTT (2,3-bis(2-methoxy-4-nitro-5- sulfo-phenyl)-2H-tetrazolium-5- FDA approved carboxanilide) assay, Amiodarone antiarrhythmic drug A. niger additive to synergistic to AMB, [76]

CLO or KET; affects cellular calcium and pH homeostasis Pitavastatin Control of blood cholesterol C. albicans, C. glabrata, Biofilm inhibition assay, (Pharmakon 1600 [77] level C. auris synergism with FLU drug library) CLSI M-27A3, synergism with ITR, VOR or FLU; / Efflux pump modulation, C. albicans, C. glabrata, inhibition of filamentation, melanin [78,79,81,82] Benzocyclane antipsychotics C. neoformans, Microsporum canis, production and biofilm formation,

derivative , Malassezia pachydermatis overexpression of lanosterol 14a- demethylase (CYP51), Efflux pump expression bis-Biguanide alexidine dihydrochloride Anticancer drug that targets a Microtiter plate assay, synergism A. fumigatus, C. albicans, [83] (AXD) mitochondrial tyrosine with FLU against biofilms; C. auris (1200 New phosphatase antifungal, antibiofilm activity Prestwick Chemical Library) CLSI M-27A3, synergism with KET, FLU or MICO, cure the murine model of C. albicans, C. glabrata, disseminated ; Beauvericin [84-87,89] , insecticidal C. parapsilosis, C. neoformans, drug efflux pump modulation,

A. fumigatus blocking the ATP-binding cassette transporters, elevating intracellular calcium and reactive oxygen species C. albicans (AMB resistant), C. dubliniensis Polyunsaturated fatty acid CLSI M27-A, synergism with FLU, C. parapsilosis, C. glabrata, [88,90] TER, CLO or AMB against biofilms; C. tropicalis

5 increase in production of prostaglandin CLSI M27-A2, adjunct therapy, Ribavirin synergism with azoles; A guanosine anti-viral agent (Prestwick Candida species fungistatic against multidrug- [94,95] against RNA or DNA virus Chemical Library) resistant C. albicans and fungicidal against C. parapsilosis Candida species, Cryptococcus species, pedrosoi, Fonsecaea monophora, CLSI M27-A3, synergism with ITR Fonsecaea nubica, Cladophialophora carrionii, (C. carrionii); Auranofin Anti-rheumatoid, arthritis [91,92] verrucosa, Rhinocladiela similis, Mia40-Erv1 pathway (a disulfide var. heteromorpha, relay system in mitochondria) Exophiala dermatitidis C. albicans, C. glabrata, CLSI M27-A3 (), C. krusei, C. parapsilosis, Auranofin Anti-rheumatoid arthritis M38-A2 (filamentous fungi), [91,93] C. neoformans, Blastomyces dermatitidis, synergism with ITR Cladophialophora carrionii C. albicans, C. auris, A. fumigatus, CLSI M27-A3, Alexidine Anticancer drug targeting A. flavus, A. niger, Aspergillus calidoustus, 384-well plates high throughput dihydrochloride mitochondrial [83,96] F. solani, F. oxysporum, R. oryzae, assay, potentiation of (Prestwick tyrosine phosphatase Lomentos poraprolificans, FLU and AMB, Chemical Library) (mitochondrial apoptosis) antibiofilm activity , Bifonazole, , Cetylpyridinium chloride, Alexidine, C. neoformans, C. albicans, A. fumigatus, Microfluidic, luciferase-based, mice Helminth treatment, Otilonium A. flavus, F. chlamydosporum, germination assay, CLSI M27‐A3, Anti-cancer, bromide, F. oxysporum, F. proliferatum, EUCAST E.DEF 9.3, synergism with [97-100,105] Irritable bowel syndrome Benzethonium F. solani, F. verticillioides, VOR or AMB (Fusarium species); treatment, etc. chloride, Pneumocystis carinii/jiroveci inhibition of germination , Temsirolimus, Disulfiram (L1300 Selleck Library)

6 Exserohilum rostratum, A. fumigatus, A. flavus, A. nidulans, A. niger, , A. terreus, C. neoformans, C. tropicalis, High throughput ATP content Anti-parasitic, , S. cerevisiae, Malassezia furfur, assay, synergism of Tacrolimus with [101- Immuno-suppressive, Floxuridine Malassezia globose, Rhizopus delemar ISA, ITR, FLU or KET; 104,106,108,109] antimetabolite (LOPAC libraries) R. arrhizus, R. microsporus affects ATP level Lichtheimia corymbifera, Lichtheimia ramosa M. circinelloides, R. pusillus Flubendazol, , C. neoformans, Cryptococcus deuterogattii, nisoldipine, Anthelmintic, Candida species (including C. albicans, C. CLSI M27‐A3, synergism with FLU, [66,107,110- Anti-hypertensive, glabrata), Saccharomyces, ITR or AMB 112,114,115] (Screen-Well Enzo blocker Aspergillus species (including A. fumigatus, library of 640 A. flavus, A. niger) compounds) CLSI M27‐A3, antibiofilm, Twenty-one synergism with FLU in C. elegans sulfonamide Antibacterial drugs C. albicans [113] model; drugs reversal of resistance, C. auris, C. albicans, C. neoformans, CLSI M27-A3, iodoquinol synergism C. gatti, Cladophialophora carrionii with ITR or TER, Phialophora verrucose, Fonsecaea monophora microemulsion with Fonsecaea nubica, Rhinocladiela similis AMB or encapsulation in alginate, Iodoquinol, Exophiala jeanselmei var. heteromorpha antibiofilm (S. schenkii), Miltefosine Exophiala dermatitidis, Drug candidates inhibit posadasii [91,116-120] (Pathogen Box® Lomentospora prolificans, (filamentous phase), Histoplasma chemical library) , , capsulatum (filamentous and yeast Histoplasma capsulatum, A. fumigatus, phases); Aspergillus ustus, A. flavus, miltefosine inhibits both planktonic Aspergillus section Nigri, growth and biofilm formation S. apiospermum, F. solani EUCAST, microtiter plate assay, biofilm inhibition assay; synergism C. neoformans, C. albicans, Quinine with FLU; Anti-parasite A. fumigatus, Rhizoctonia solani, [121,125] synergistic mis-translation in Zymoseptoria tritici, Botrytis cinerea quinine plus hygromycin co- application Quinacrine Anti-protozoan drug C. albicans, C. neoformans CLSI M27-A3, Antibiofilm assay; [122,123]

7 synergism with CAS & AMB, antibiofilm activity via vacuolar alkalinization, endocytosis inhibition; impaired filamentation Pyrvinium pamoate, Antibiofilm assay via XTT assay; Antiseptic, anti- C. albicans, affects biofilm formation, pyrvinium Benzbromarone, inflammatory, anthelmintic, Exophiala dermatitidis pamoate synergism with POS, ITR, [31,33,124] Auranofin uricosuric drug, etc. VOR (E. dermatitidis) & interference (Prestwick of metal homeostasis (C. albicans) Chemical Library) NSC319726 CLSI M-27A, (Thiosemicarbazo Candida species,A. fumigatus, A. flavus, Drop plate assays, E-tests; ne) C. neoformans, Paracoccidioides brasiliensis, ergosterol biosynthesis & ribosomal Anti-cancer drug [126-130,134] (NIH/NCI Fusarium species biogenesis inhibition, synergism compound with azoles and CAS, library) antiaflatoxigenic Mycophenolic acid, Disulfiram, Immune-suppression, E-test, drug diffusion susceptibility Fluvastatin, deterrent of C. albicans, C. neoformans, testing, checkerboard assay; Octodrine, etc. consumption, Trichophyton species, [131-133,135] synergism with AMB inhibits (1581 FDA antihyperlipidemic, A. niger, A. flavus, Aspergillus brasiliensis nucleotide biosynthesis approved drug decongestant, etc. Library) Human neutrophils, epithelial cell adhesion & invasion assays; C. albicans, Pythium insidiosum, greater susceptibility to oxidative stress, Deferasirox Iron chelator [136,137,139] A. fumigatus, R. oryzae synergism with MICA (P. insidiosum), deferasirox improved POS activity with pulmonary CLSI M38-A2, murine model, macrophage assay; C. neoformans, NAC synergism with AMB, TER, Scedosporium aurantiacum, decreased capsule size, zeta N- Scedosporium boydii, [138,140] Anti- drug potential, superoxide dismutase (NAC) Pseudallescheria angusta, activity, lipid peroxidation; reduced Pseudallescheria ellipsoidea fungal burden in lungs & brain and

concentrations of pro-inflammatory cytokines in the lungs

8 Clioquinol, Alexidine Aspergillus species (including A. terreus), dihydrochloride, Fusarium species (including , Anti-protozoal, F. solani) Hexachloro- Scedosporium/Lomentospora, Rhizopus Anti-bacterial drug, CLSI M38-A; phene, microsporus, Lichtheimia species [83,96,141,144] Cationic detergent (zinc synergism with POS Thonzonium (Multidrug resistant), C. albicans, C. glabrata, chelator) bromide C. parapsilosis, C. auris, C. tropicalis, C. (Prestwick guilliermondii, T. harzianum Chemical Library) CLSI M27-A3, biofilm, hyphal and planktonic growth inhibition, Panobinostat Pan-histone deacetylase C. albicans Galleria mellonella infection model, [143] (FDA-approved) inhibitor, anti-tumor agent synergism with FLU; metacaspase activation (apoptosis) C. EXPERIMENTAL, DRUG/COMPOUND ALONE Anti-cardiovascular disease, Ebselen C. tropicalis, C. albicans, CLSI M27-A3, biopolymeric arthritis, stroke, [145] C. parapsilosis encapsulation atherosclerosis, cancer, etc. CLSI M-27A3, C. elegans infection assay, S. cerevisiae Anti-cardiovascular disease, C. albicans, C. glabrata, haplo-insufficiency validation; Ebselen arthritis, stroke, C. tropicalis, C. parapsilosis, [142] depletes intracellular glutathione atherosclerosis, cancer, etc. C. neoformans, C. gattii levels; reactive oxygen species production Antibiofilm tests, CLSI M27-A3; Review: affects iron & calcium homeostasis, Adjuvants Menopausal hormone calcineurin & calmodulin, (Plant extracts, therapy, Yeast (including C. albicans, serotonin reuptake, anti- essential oils, Prophylactic antianginal C. glabrata, C. neoformans) and filamentous , histone deacetylase, [49,68,147] peptides, agent, fungal pathogens efflux pump, Drospirenon, Anti-cancer ABC & MFS transporter, Perhexiline, biofilm formation, heat shock Toremifene, etc.) protein 90 (Hsp90) 4-[6-[[2-(4- Microdilution and fluorescent Anti- Plasmodium C. gatti, C. neoformans, [148] aminophenyl)-3H- microscopic analysis; drug C. albicans, L. prolificans benzimidazol-5- localization to the nuclei,

9 yl]methyl]-1H- apoptosis-like cell death benzimidazol-2- yl]aniline (Malaria Box) Cryptococcal meningitis, Candida species (including C. albicans, C. parapsilosis, C. tropicalis), Pseudallescheria species, CLSI M27-A3, (Trifluoperazine) Scedosporium species, checkerboard bioassays; [57,140,146,149,15 Antipsychotic drugs R. microspores var. rhizopodiformis calmodulin antagonism, modulating 0] R. oryzae, Rhizopus schipperae undesired neurological effects Saksenaea vasiformis, R. miehei R. pusillus, A. corymbifera, Torulopsis glabrata Microtiter plate biofilm inhibition assay, metabolism & hyphal antipsychotic drug C. albicans [152] inhibitory assays; biofilm and hyphal inhibition CLSI M27-A3, time-kill assay; C. albicans, C. glabrata, C. auris, interfere with mitochondrial, Antimalarial drug C. neoformans, A. fumigatus, [155] vacuolar function and filamentation S. cerevisiae (virulence factor) CLSI M27-A3; Theophylline membrane damage, inhibit malate Respiratory drug C. albicans and non-albicans [151] (THP) synthase & isocitrate lyase (glyoxylate cycle) Biofilm viability & cell morphology bioassay, Galleria mellonella larvae assay; [154] Muscarinic receptor agonist C. albicans hydrochloride inhibition of C. albicans filamentation and regulation of cellular immunity. CLSI M27-A2, Treatment of neglected EUCAST EDef 7.2; tropical disease; C. neoformans [107] binding of flubendazole to onchocerciasis cryptococcal β-tubulin [153] Oxyclozanide Anthelmintic C. albicans Liquid bioassay;

10 uncoupling the mitochondrial electron transport, perturbing mitochondrial membrane potential Candida species (C. albicans, C. glabrata, C. Ebsulfur, krusei, C. parapsilosis), Broth dilution assay, time-kill assay; Antibacterial drugs [159] Ebselen Aspergillus species (A. flavus, A. nidulans, induction of reactive oxygen species A. terreus) F. oxysporum,F. graminearum, Pyrazole p21-activated protein kinase Phytopthora species,Myrothecium roridum, derivative In vitro agar assay [156,158] inhibitor Helminthosporium maydis, C. albicans,

C. krusei, C. tropicalis Microtiter bioassay; antifungal activity against Anti-helminthic C. neoformans, C. gatti [157] phagocytized C. neoformans, affected biofilms Review: Biofilm inhibition assay; 17-AAG, Hsp 90 Anti-cancer drug Candida species, Aspergillus species combination with azole without host [160] inhibitors toxicity 5-α-reductase inhibitor; Urinary biofilm assay using XTT; treatment of benign prostatic C. albicans [164] inhibition of filamentation hyperplasia Thirty-two High-throughput, multiplexed compounds Human hormone, etc. flow cytometry & dose-response [165] C. albicans (Prestwick assay; Chemical Library) induction of efflux pump Cdr1p CLSI M100–S25; anti-biofilm XTT Auranofin C. albicans, assay; Anti-rheumatoid arthritis [161] Staphylococcus aureus (bacterium) inhibition of S. aureus and C. albicans mono- and dual biofilm formation CLSI M27-A, biofilm inhibition Twenty assay, adherence inhibition screen; compounds Alcoholism medication, blocking calcium channels, [162] (Pharmakon 1600 Anti-depressant, C. albicans inhibition of a selective serotonin compound Anti-amoeba reuptake & azole-based proton library) pump inhibitor Lopinavir C. auris, CLSI M27-A3, (1547 FDA- HIV protease inhibitor C. albicans, [163] C. elegans infection model; approved C. krusei,

11 drug library) C. parapsilosis, interfere with the C. tropicalis permeation and ATP synthesis Pterostilbene, procyanidin, CLSI M27-A3; , Human disease C. albicans phosphopantetheinyl transferase [166] tea Ppt2 inhibition polyphenol (FDA-approved) Robenidine A. fumigatus, Growth curve, biofilm assay; Anticoccidial agent reating (1068 FDA- C. albicans, inhibit yeast cell growth, coccidian of [167] approved drug C. neoformans, filamentation, biofilm formation, poultry and library) S. cerevisiae and cell wall integrity pathway Immunosuppression model of murine oropharyngeal candidiasis; reduction in survival in neutrophil FDA-approved iron chelator Deferasirox C. albicans phagosomes, greater susceptibility [137] treating iron overload to oxidative stress, reduced adhesion to and invasion of oral epithelial cells Murine model of disseminated ; FDA-approved anti-cancer C. gattii, cisplatin inhibited Prp8 intein Cisplatin [168] drug C. neoformans splicing, significantly inhibits the growth of Prp8 intein-containing C. neoformans and C. gattii Halogenated Microtiter plate assay; , FDA-approved anthelmintic C. neoformans, C. albicans, antifilamentation, antibiofilm Niclosamide in humans [169,170] C. auris (multidrug-resistant) activities (678 Maybridge

collection) 1 Drug abbreviations: (AMB), 5- (5FC), (FLU), (ITR), (VOR), (POS), isavuconazole (ISA), (KET), (MICO), (CLO), (CAS), (MICA), anidulafungin (ANI), (TER). 2 CLSI, Clinical & Laboratory Standards Institute. 3 EUCAST, European Committee on Antimicrobial Susceptibility Testing.

12

13

Top View