Antifolates as antimycotics?

Navarro-Martínez, María Dolores; Cabezas‐Herrera, Juan; Rodrı́guez-López, José Neptuno

doi:10.1016/j.ijantimicag.2006.07.012

Cited by 34 publications

(13 citation statements)

References 18 publications

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“…strated that MTX does not accumulate within C. albicans yeast cells at neutral pH (28) and may therefore account for the pH-dependent antifungal activity.…”

Section: Figmentioning

confidence: 99%

“…To distinguish between these possibilities, we attempted to directly inhibit Dfr1p using methotrexate. Previous reports have indicated that MTX lacks antifungal activity against C. albicans (28)(29)(30), despite potent inhibition of purified fungal DHFR in biochemical assays (34). However, we recently reported that MTX has relatively potent and on-target activity upon whole C. albicans cells in unbuffered yeast nitrogen base (YNB) medium (35).…”

Section: Figmentioning

confidence: 99%

“…The pH-dependent antifungal activity of methotrexate is likely due to differential uptake. While MTX has been shown to inhibit fungal DHFR in cell-free biochemical assays using purified enzyme, it has also been reported to lack antifungal activity (28)(29)(30). Given that these previous studies used RPMI 1640 pH 7 medium, we sought to account for the antifungal activity we observed in unbuffered YNB medium.…”

Section: Figmentioning

confidence: 99%

“…Although these drugs were not specifically developed to target the folate biosynthetic enzymes of Pneumocystis, they provide clinical evidence that targeted inhibition of the folate (FOL) pathway can provide an effective intervention strategy to treat invasive mycoses. However, the conventional antifolate drugs developed for bacterial or protozoan DHPS or DHFR, or even human DHFR, have little or no antifungal activity upon the major human fungal pathogens (28)(29)(30), either because of divergence of the fungal enzyme structures or permeability issues that prevent antifolates from entering fungal cells (28). Furthermore, until now, no published study has unequivocally determined if the core components of the FOL pathway are required by infectious fungi to cause disease within a mammalian host and are therefore valid and potentially efficacious targets for antifungal development.…”

mentioning

confidence: 99%

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Dihydrofolate Reductase Is a Valid Target for Antifungal Development in the Human Pathogen Candida albicans

DeJarnette

Luna-Tapia²,

Estredge

et al. 2020

mSphere

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While the folate biosynthetic pathway has provided a rich source of antibacterial, antiprotozoal, and anticancer therapies, it has not yet been exploited to develop uniquely antifungal agents. Although there have been attempts to develop fungal-specific inhibitors of dihydrofolate reductase (DHFR), the protein itself has not been unequivocally validated as essential for fungal growth or virulence. The purpose of this study was to establish dihydrofolate reductase as a valid antifungal target. Using a strain with doxycycline-repressible transcription of DFR1 (PTETO-DFR1 strain), we were able to demonstrate that Dfr1p is essential for growth in vitro. Furthermore, nutritional supplements of most forms of folate are not sufficient to restore growth when Dfr1p expression is suppressed or when its activity is directly inhibited by methotrexate, indicating that Candida albicans has a limited capacity to acquire or utilize exogenous sources of folate. Finally, the PTETO-DFR1 strain was rendered avirulent in a mouse model of disseminated candidiasis upon doxycycline treatment. Collectively, these results confirm the validity of targeting dihydrofolate reductase and, by inference, other enzymes in the folate biosynthetic pathway as a strategy to devise new and efficacious therapies to combat life-threatening invasive fungal infections. IMPORTANCE The folate biosynthetic pathway is a promising and understudied source for novel antifungals. Even dihydrofolate reductase (DHFR), a well-characterized and historically important drug target, has not been conclusively validated as an antifungal target. Here, we demonstrate that repression of DHFR inhibits growth of Candida albicans, a major human fungal pathogen. Methotrexate, an antifolate, also inhibits growth but through pH-dependent activity. In addition, we show that C. albicans has a limited ability to take up or utilize exogenous folates as only the addition of high concentrations of folinic acid restored growth in the presence of methotrexate. Finally, we show that repression of DHFR in a mouse model of infection was sufficient to eliminate host mortality. Our work conclusively establishes DHFR as a valid antifungal target in C. albicans.

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“…strated that MTX does not accumulate within C. albicans yeast cells at neutral pH (28) and may therefore account for the pH-dependent antifungal activity.…”

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Dihydrofolate Reductase Is a Valid Target for Antifungal Development in the Human Pathogen Candida albicans

DeJarnette

Luna-Tapia²,

Estredge

et al. 2020

mSphere

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“…Many immunomodulatory drugs have conserved targets in fungal pathogens; for example, calcineurin is crucial for the survival during membrane stress ( Cruz et al, 2002 ), and calcineurin inhibitors (cyclosporine A (CsA) and Fk506) have antifungal properties ( Steinbach et al, 2007 ; Li et al, 2015 ; Denardi et al, 2015 ; Yu, Chang & Chen, 2015 ). Methotrexate (MTX), which blocks folic acid metabolism, also has antifungal properties, as it inhibits ergosterol production in C. albicans and makes it more susceptible to azoles ( Navarro-Martínez, Cabezas-Herrera & Rodríguez-López, 2006 ). Mycophenolic acid (MPA) targets inosine-5′-monophosphate dehydrogenase, which is a crucial enzyme for the de novo synthesis of guanine nucleotides ( Shah & Kharkar, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Synergistic and antagonistic effects of immunomodulatory drugs on the action of antifungals againstCandida glabrataandSaccharomyces cerevisiae

Tome

Zupan

Tomičić

et al. 2018

PeerJ

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Candidemia and other forms of invasive fungal infections caused by Candida glabrata and to a lesser extent Saccharomyces cerevisiae are a serious health problem, especially if their steadily rising resistance to the limited range of antifungal drugs is taken into consideration. Various drug combinations are an attractive solution to the resistance problem, and some drug combinations are already common in the clinical environment due to the nature of diseases or therapies. We tested a few of the common antifungal-immunomodulatory drug combinations and evaluated their effect on selected strains of C. glabrata and S. cerevisiae. The combinations were performed using the checkerboard microdilution assay and interpreted using the Loewe additivity model and a model based on the Bliss independence criterion. A synergistic interaction was confirmed between calcineurin inhibitors (Fk506 and cyclosporine A) and antifungals (fluconazole, itraconazole, and amphotericin B). A new antagonistic interaction between mycophenolic acid (MPA) and azole antifungals was discovered in non-resistant strains. A possible mechanism that explains this is induction of the Cdr1 efflux pump by MPA in C. glabrata ATCC 2001. The Pdr1 regulatory cascade plays a role in overall resistance to fluconazole, but it is not essential for the antagonistic interaction. This was confirmed by the Cgpdr1Δ mutant still displaying the antagonistic interaction between the drugs, although at lower concentrations of fluconazole. This antagonism calls into question the use of simultaneous therapy with MPA and azoles in the clinical environment.

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Antibacterial, Antifungal, Phytotoxic, and Genotoxic Properties of Two Complexes of Ag^I with Sulfachloropyridazine (SCP): X‐ray Diffraction of [Ag(SCP)]_n

et al. 2014

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We report the synthesis, characterization, antibacterial and antifungal activities, phytotoxicity, and genotoxicity of two new complexes of silver(I) with sulfachloropyridazine (SCP), one of which is heteroleptic with SCP and SCN(-) ligands (Ag-SCP-SCN), the other of which is homoleptic (Ag-SCP); furthermore, the crystal structure of the homoleptic complex is disclosed. The heterocyclic N atom nearest to the Cl atom and the N(sulfonamide) atom could be coordination sites for the silver ion in the Ag-SCP-SCN complex. The Ag-SCP complex is a polymeric compound with metal-metal bonds, and the heterocyclic and sulfonamide N atoms are points of coordination for Ag(I) . Both complexes showed activity against all the tested bacteria, and in the cases of Escherichia coli and Pseudomonas aeruginosa, the action was better than that of SCP. In all cases, both silver-SCP complexes showed better antifungal activity than SCP, which was inactive against the tested fungi. Notably, the activity against P. aeruginosa, a nosocomial multidrug-resistant pathogen, was better than that of the reference antibiotic cefotaxim. Both silver-sulfa complexes displayed moderate activity against the tested yeast, especially for C. neoformans, which is an important fact considering the incidence of cryptococcosis, mainly in immune-deficient patients. No chromosomal aberrations were observed with the Allium cepa test, which is auspicious for further study of these complexes as potential drugs.

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Antifolates as antimycotics?

Cited by 34 publications

References 18 publications

Dihydrofolate Reductase Is a Valid Target for Antifungal Development in the Human Pathogen Candida albicans

Dihydrofolate Reductase Is a Valid Target for Antifungal Development in the Human Pathogen Candida albicans

Synergistic and antagonistic effects of immunomodulatory drugs on the action of antifungals againstCandida glabrataandSaccharomyces cerevisiae

Antibacterial, Antifungal, Phytotoxic, and Genotoxic Properties of Two Complexes of Ag^I with Sulfachloropyridazine (SCP): X‐ray Diffraction of [Ag(SCP)]_n

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Antifolates as antimycotics?

Cited by 34 publications

References 18 publications

Dihydrofolate Reductase Is a Valid Target for Antifungal Development in the Human Pathogen Candida albicans

Dihydrofolate Reductase Is a Valid Target for Antifungal Development in the Human Pathogen Candida albicans

Synergistic and antagonistic effects of immunomodulatory drugs on the action of antifungals againstCandida glabrataandSaccharomyces cerevisiae

Antibacterial, Antifungal, Phytotoxic, and Genotoxic Properties of Two Complexes of AgI with Sulfachloropyridazine (SCP): X‐ray Diffraction of [Ag(SCP)]n

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Product

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Antibacterial, Antifungal, Phytotoxic, and Genotoxic Properties of Two Complexes of Ag^I with Sulfachloropyridazine (SCP): X‐ray Diffraction of [Ag(SCP)]_n