Dual action antifungal small molecule modulates multidrug efflux and TOR signaling
Open accessAbstract
There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. We establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug resistance, and renders resistant pathogens responsive to treatment in mammalian infection models. Harnessing genome sequencing of beauvericin-resistant mutants, affinity purification of a biotinylated beauvericin analog, and biochemical and genetic assays reveals that beauvericin blocks multidrug efflux and inhibits the global regulator TORC1 kinase, thereby activating protein kinase CK2 and inhibiting the molecular chaperone Hsp90. Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux, thereby impeding resistance to the drug combination. Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for fungal infectious disease that evades resistance.
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Written from the paper’s full text.
TL;DR
Beauvericin potentiates azole antifungals against major fungal pathogens by dual inhibition of multidrug efflux and TORC1 signaling, leading to CK2 activation and Hsp90 impairment. This combination blocks resistance emergence and shows therapeutic benefit in mammalian infection models.
Key findings
- Beauvericin had no antifungal activity alone but enhanced azole efficacy against *S. cerevisiae*, *C. albicans*, *C. neoformans*, and *A. fumigatus*; against *C. albicans*, fluconazole–beauvericin synergy gave a fractional inhibitory concentration index (FICI) of <0.1 and converted fungistatic azole activity into a fungicidal combination.
- Beauvericin blocked emergence of azole resistance: plating 1×10⁵ *C. albicans* cells on 32 μg/ml fluconazole with 20 μg/ml beauvericin prevented resistant colonies.
- Beauvericin-resistant mutants selected at 100 μg/ml beauvericin in transporter-deficient backgrounds had mutations in *PDR5* (five mutants) or *CKB1*/*CKB2* (ten mutants, six independent events); Pdr5 substitutions enabled beauvericin efflux while impairing azole efflux.
- Affinity purification with biotinylated beauvericin identified 12 proteins at FDR ≤1%, including Cka2 and Tor2; beauvericin inhibited TORC1-dependent Sch9 phosphorylation, activated CK2, impaired Hsp90 clients, and in mice infected with 5×10⁶ *C. albicans*, beauvericin (4 mg/kg) plus fluconazole (0.5 mg/kg) gave potent therapeutic benefit; in a rat catheter biofilm model, the combination sterilized catheters.
Methods
- Drug combination and resistance assays used azole Etest strips, checkerboard matrices, broth microdilution MIC testing, and spotting assays with *S. cerevisiae*, *C. albicans*, *C. neoformans*, and *A. fumigatus*, including *C. albicans* clinical isolates.
- Target identification combined selection of beauvericin-resistant mutants in ABC-transporter-deficient backgrounds, whole-genome sequencing, Sanger validation, and affinity purification coupled to mass spectrometry with a biotinylated beauvericin analog, analyzed by SAINTexpress.
- Mechanistic assays included radiolabeled [³H]-fluconazole accumulation, rhodamine-6G transport and accumulation, Pdr5 ATPase activity, CK2 kinase assays with Sic1 phosphorylation, qRT-PCR, Sch9/Ypk1 and Hog1 western blots, β-galactosidase reporters, and murine/rat infection models.
Limitations
- The paper does not state a dedicated limitations section.
- Evident from the text: the ABC16 selection experiment was performed once, and the murine disseminated-infection model used no blinding.
- Some target conclusions are indirect: excess unmodified beauvericin did not compete the biotinylated analog from most proteins, including Cka2, and beauvericin did not alter recombinant human CK2 activity, leaving fungal-specific or indirect effects unresolved.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 17 cited sources checked · 0 supported · 0 flagged
- Findingown data
Beauvericin inhibits TORC1 kinase.
“inhibits the global regulator TORC1 kinase”
- Also stated in: § Beauvericin activates CK2 and inhibits TORC1 · plain
“Beauvericin caused a significant reduction in Sch9 phosphorylation and a modest reduction in Ypk1 phosphorylation (Fig. 4e, Supplementary Fig. 10).”
- Also stated in: § Discussion · plain
“beauvericin inhibits TORC1”
Quote in the paperSubstantial claim - Also stated in: § Beauvericin activates CK2 and inhibits TORC1 · plain
- Findingown data
All ten beauvericin-resistant ABC16 mutants had mutations in CKB1 or CKB2.
“Whole genome sequencing of ten resistant mutants revealed that each harboured a mutation in either CKB1 or CKB2, encompassing six independent mutational events (Fig. 3a).”
Quote in the paperSubstantial claim - Findingown data
Beauvericin and fluconazole are synergistic against C. albicans with a fractional inhibitory concentration index (FICI) of <0.1.
“We used a dose response matrix (checkerboard) to corroborate the synergy between the azole fluconazole and beauvericin against C. albicans, with a fractional inhibitory concentration index (FICI) of <0.1 (Fig. 1b).”
Quote in the paperSubstantial claim - Findingown data
Beauvericin reduces azole resistance of C. albicans clinical isolates.
“Beauvericin reduced resistance of all isolates (Fig. 1c), with cidality of the combination evident at higher azole concentrations”
Quote in the paperSubstantial claim - Findingown data
Beauvericin at 20 μg/ml blocks the emergence of fluconazole resistance in C. albicans.
“Inclusion of beauvericin in the medium at a concentration that did not impair growth (20 μg/ml) blocked the emergence of resistance (Fig. 1d).”
Quote in the paperSubstantial claim
- Findingown data
Deletion of either CKA1 or CKA2 from the ABC16 strain confers partial resistance to beauvericin.
“deletion of either CKA1 or CKA2 from the ABC16 strain confers partial resistance to beauvericin (Supplementary Fig. 6)”
Quote in the paperSubstantial claim - Findingown data
Beauvericin transforms azole fungistatic activity into a fungicidal combination.
“Transferring cells from the checkerboard onto drug-free rich medium revealed that beauvericin transforms azole fungistatic activity into a fungicidal combination (Fig. 1b).”
Quote in the paperSubstantial claim - Findingown data
Beauvericin increases Sic1 phosphorylation in vitro.
“Beauvericin increased Sic1 phosphorylation, suggesting that it activates CK2 (Fig. 4b and Supplementary Fig. 8a).”
Quote in the paperSubstantial claim - Findingown data
Tor2 was identified in all three AP-MS experiments.
“Tor2 was identified in all three experiments”
Quote in the paperSubstantial claim - Findingown data
Beauvericin potentiates azole antifungal activity against Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and Saccharomyces cerevisiae.
“potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens”
- Also stated in: § Beauvericin enhances azole efficacy and blocks resistance · plain
“Beauvericin had no antifungal activity alone, but enhanced azole efficacy against the model yeast Saccharomyces cerevisiae and fungal pathogens C. albicans, C. neoformans, and A. fumigatus (Fig. 1a).”
- Also stated in: § Introduction · plain
“Beauvericin enhances azole efficacy against the leading human fungal pathogens, Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans”
Quote in the paperSubstantial claim- Rests on an assumption: The mechanism of beauvericin action (inhibition of Pdr5, TORC1, CK2, and Hsp90) identified in S. cerevisiae and C. albicans is conserved in other human fungal pathogens such as A. fumigatus and C. neoformans.
- Also stated in: § Beauvericin enhances azole efficacy and blocks resistance · plain
- Findingown data
Beauvericin blocks multidrug efflux.
“beauvericin blocks multidrug efflux”
- Also stated in: § Beauvericin enhances azole intracellular accumulation · plain
“Beauvericin inhibited Pdr5 ATPase activity and transport of rhodamine-6G (Fig. 2e).”
- Also stated in: § Discussion · plain
“Beauvericin inhibits multidrug efflux”
Quote in the paperSubstantial claim - Also stated in: § Beauvericin enhances azole intracellular accumulation · plain
- Findingown data
Deletion of either CKB1 or CKB2 in the ABC16 background confers full beauvericin resistance.
“Deletion of either CKB1 or CKB2 in the ABC16 background conferred full beauvericin resistance, suggesting that the mutations identified cause loss of function of CK2 subunits (Fig. 3b).”
Quote in the paperSubstantial claim - Findingown data
Cka2 was identified as a top interacting protein in two AP-MS experiments.
“Two experiments identified Cka2 as a top interacting protein, corroborating the link between beauvericin and CK2.”
Quote in the paperSubstantial claim - Findingown data
Expression of PDR5G538R as the only PDR5 allele in a yor1Δ mutant confers full beauvericin resistance.
“Expression of PDR5G538R as the only PDR5 allele in a yor1Δ mutant conferred full beauvericin resistance (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data
Beauvericin alone has no antifungal activity.
“Beauvericin had no antifungal activity alone”
- Also stated in: § Discussion · plain
“it has little antifungal activity alone due to efflux mediated by the ABC transporter Yor1”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Deleting PDR5 in the yor1Δ strain does not confer beauvericin resistance.
“These are not loss-of-function mutations, as deleting PDR5 in the yor1Δ strain did not confer beauvericin resistance (Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data
Beauvericin is not a substrate of wild-type Pdr5.
“Beauvericin is not a substrate of wild-type Pdr5, as deletion of PDR5 did not enhance beauvericin susceptibility (Fig. 2a,b).”
Quote in the paperSubstantial claim - Findingown data
Only the S. cerevisiae strain lacking YOR1 among 16 ABC transporter deletion strains is sensitive to beauvericin.
“We screened S. cerevisiae strains each lacking one of 16 ATP-binding cassette (ABC) transporter genes14, and found that only the strain lacking YOR1 was sensitive to beauvericin (Supplementary Fig. 2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Suzuki, Y. et al. Knocking out multigene redundancies via cycles of sexual assortment and fluorescence selection. Nat. Methods 8, 159–164 (2011). source
Not checked in the free run.
- Findingown data
Twelve proteins were identified in at least two of three AP-MS experiments.
“Twelve proteins were identified in at least two of the three experiments (Fig. 4a).”
Quote in the paperNot a substantial claim - Findingown data
All five beauvericin-resistant yor1Δ mutants had nonsynonymous mutations in PDR5.
“Each of the resistant mutants had nonsynonymous mutations in the ABC transporter gene PDR5 (Fig. 2a), which mapped to transmembrane domains or proximal regions.”
Quote in the paperSubstantial claim - Findingown data
Beauvericin causes increased fluconazole accumulation in S. cerevisiae and C. albicans.
“We found that beauvericin caused increased fluconazole accumulation in S. cerevisiae and C. albicans (Fig. 2c, bottom panel).”
Quote in the paperSubstantial claim - Findingown data
Substitutions in Pdr5 that enable beauvericin efflux impair azole efflux.
“Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux”
- Also stated in: § Pdr5 substitutions enable beauvericin efflux · plain
“Representative mutants yor1Δ R1 and R5 show increased accumulation of radiolabelled azole (Fig. 2c, top panel).”
- Also stated in: § Discussion · plain
“substitutions in the ABC transporter Pdr5 that alter substrate specificity and enable beauvericin efflux concomitantly impair azole efflux”
Quote in the paperSubstantial claim - Also stated in: § Pdr5 substitutions enable beauvericin efflux · plain
- Findingown data
Beauvericin partially blocks calcineurin activation in response to fluconazole.
“Activation of calcineurin in response to fluconazole was blocked by the calcineurin inhibitor FK506, and partially blocked by the Hsp90 inhibitor geldanamycin and by beauvericin (Fig. 5a).”
Quote in the paperSubstantial claim - Findingown data
In a murine model of C. albicans disseminated infection, the combination of beauvericin and fluconazole has potent therapeutic benefit.
“As a combination, there was potent therapeutic benefit of beauvericin and fluconazole (Fig. 6a).”
Quote in the paperSubstantial claim - Findingown data
Beauvericin suppresses the antifungal activity of rapamycin.
“We observed potent antagonism, such that beauvericin suppressed the antifungal activity of rapamycin (Fig. 4c).”
Quote in the paperSubstantial claim - Findingown data
Beauvericin does not directly affect human CK2 activity in vitro.
“Addition of either CK2α or CK2α2β2 caused increased Sic1 phosphorylation that was not altered by beauvericin (Supplementary Fig. 8c).”
Quote in the paperSubstantial claim - Findingown data
Deletion of CKB1 or CKA2 reduces the impact of beauvericin on Hog1 activation.
“deletion of CKB1 or CKA2 reduced the impact of beauvericin on Hog1 activation (Fig. 5c).”
Quote in the paperSubstantial claim - Findingown data
In a rat central venous catheter model of C. albicans biofilm infection, the combination of beauvericin and fluconazole sterilized the catheter.
“As a drug combination, beauvericin and fluconazole sterilized the catheter (Fig. 6b,c).”
Quote in the paperSubstantial claim - Findingown data
Beauvericin potently induces the heat-shock response in C. albicans.
“Beauvericin potently induced the HSR (Fig. 5b), consistent with a repressive effect on Hsp90 function.”
Quote in the paperSubstantial claim - Findingown data
Beauvericin impairs Hog1 activation in response to osmotic stress in the S. cerevisiae ABC16 strain.
“beauvericin impaired Hog1 activation in the ABC16 strain (Fig. 5c, Supplementary Fig. 11).”
Quote in the paperSubstantial claim - Interpretationown data
Yor1 effluxes beauvericin.
“This suggests that Yor1 effluxes beauvericin, and enables selection of resistant mutants.”
Quote in the paperSubstantial claim - Interpretationown data
Beauvericin inhibits the molecular chaperone Hsp90.
“inhibiting the molecular chaperone Hsp90”
- Also stated in: § Beauvericin impairs Hsp90 function · hedged
“Beauvericin potently induced the HSR (Fig. 5b), consistent with a repressive effect on Hsp90 function.”
- Also stated in: § Discussion · plain
“beauvericin causes inhibition of Hsp90 function”
Quote in the paperSubstantial claim - Also stated in: § Beauvericin impairs Hsp90 function · hedged
- Interpretationown data
PDR5 mutations alter Pdr5 substrate specificity, enabling beauvericin efflux at the expense of other substrates.
“Together, this suggests that Pdr5 substrate specificity is altered in the mutants, enabling beauvericin efflux at the expense of other substrates.”
Quote in the paperSubstantial claim - Interpretationreasoning
Beauvericin exerts antifungal activity via CK2.
“suggesting that beauvericin exerts antifungal activity via CK2.”
Quote in the paperSubstantial claim - Interpretationown data
Loss of function of CK2 subunits confers beauvericin resistance.
“Thus, loss of function of CK2 subunits confers beauvericin resistance, suggesting that beauvericin exerts antifungal activity via CK2.”
Quote in the paperSubstantial claim - Interpretationown data
Dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for fungal infectious disease that evades resistance.
“Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for fungal infectious disease that evades resistance.”
- Also stated in: § Introduction · boosted
“Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful and broadly effective therapeutic strategy for fungal infectious disease.”
- Also stated in: § Discussion · boosted
“Our findings reveal that dual targeting of multidrug efflux and TOR signaling provides a powerful strategy to enhance antifungal efficacy, impede drug resistance, and render resistant pathogens responsive to treatment.”
Quote in the paperSubstantial claim- Rests on an assumption: The mechanism of beauvericin action (inhibition of Pdr5, TORC1, CK2, and Hsp90) identified in S. cerevisiae and C. albicans is conserved in other human fungal pathogens such as A. fumigatus and C. neoformans.
- Rests on an assumption: The therapeutic benefit of the beauvericin-fluconazole combination in mammalian infection models is mediated by the same dual targeting of multidrug efflux and TOR signaling.
- Rests on an assumption: The Pdr5 substitutions that enable beauvericin efflux and impair azole efflux are representative of resistance mechanisms that would emerge in clinical settings.
- Also stated in: § Introduction · boosted
- Interpretationreasoning
Beauvericin must have an additional target beyond Pdr5.
“Beauvericin must have an additional target beyond Pdr5 to mitigate antifungal activity in the absence of azoles, as Pdr5 is not required for viability of the wild type or yor1Δ mutant (Fig. 2).”
Quote in the paperSubstantial claim - Interpretationown data
Beauvericin activates protein kinase CK2.
“activating protein kinase CK2”
- Also stated in: § Beauvericin activates CK2 and inhibits TORC1 · hedged
“Beauvericin increased Sic1 phosphorylation, suggesting that it activates CK2 (Fig. 4b and Supplementary Fig. 8a).”
- Also stated in: § Discussion · plain
“stimulating protein kinase CK2”
Quote in the paperSubstantial claim - Also stated in: § Beauvericin activates CK2 and inhibits TORC1 · hedged
- Interpretationown data
Pdr5 substitutions that enable beauvericin efflux impede resistance to the drug combination.
“thereby impeding resistance to the drug combination”
- Also stated in: § Pdr5 substitutions enable beauvericin efflux · plain
“Thus, mutations in PDR5 that enable beauvericin efflux impede azole efflux, thereby blocking the emergence of resistance to the drug combination.”
- Also stated in: § Discussion · plain
“thereby impeding the emergence of resistance to the drug combination.”
Quote in the paperSubstantial claim- Rests on an assumption: The Pdr5 substitutions that enable beauvericin efflux and impair azole efflux are representative of resistance mechanisms that would emerge in clinical settings.
- Also stated in: § Pdr5 substitutions enable beauvericin efflux · plain
- Premisecitation
Hsp90 regulates drug resistance by stabilizing the protein phosphatase calcineurin.
“Hsp90 regulates drug resistance by stabilizing the protein phosphatase calcineurin9,10”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [9] Cowen, L.E. & Lindquist, S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309, 2185–2189 (2005). source
Not checked in the free run.
- cites [10] Singh, S.D. et al. Hsp90 governs echinocandin resistance in the pathogenic yeast Candida albicans via calcineurin. PLoS Pathog. 5, e1000532 (2009). source
Not checked in the free run.
- Interpretationown data
Beauvericin exerts a repressive effect on Hsp90 via activation of CK2 signaling.
“Thus, beauvericin exerts a repressive effect on Hsp90 via activation of CK2 signaling, providing a mechanism by which it abrogates azole resistance and creates a fungicidal drug combination (Fig. 5d).”
Quote in the paperSubstantial claim - Interpretationown data
Beauvericin has profound therapeutic benefits in combination with azoles in mammalian infection models.
“Thus, beauvericin has profound therapeutic benefits in combination with azoles in mammalian infection models.”
Quote in the paperSubstantial claim- Rests on an assumption: The therapeutic benefit of the beauvericin-fluconazole combination in mammalian infection models is mediated by the same dual targeting of multidrug efflux and TOR signaling.
- Premisecitation
TORC1 regulates phosphorylation of CK2 via the effector kinase Kns1.
“TORC1 regulates phosphorylation of CK2 via the effector kinase Kns121.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Sanchez-Casalongue, M.E. et al. Differential phosphorylation of a regulatory subunit of protein kinase CK2 by target of rapamycin complex 1 signaling and the Cdc-like kinase Kns1. J. Biol. Chem. 290, 7221–7233 (2015). source
Not checked in the free run.
- May combine two claims. 13
- Classified as probably not a substantial claim. 20
May combine two claims.
Findingown dataPdr5 deletion blocks beauvericin-induced fluconazole accumulation and drug synergy.
“Both the increase in fluconazole accumulation and the drug synergy were blocked in an S. cerevisiae strain lacking Pdr5 (Supplementary Fig. 5 and Fig. 2d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBeauvericin inhibits Pdr5 ATPase activity and transport of rhodamine-6G.
“Beauvericin inhibited Pdr5 ATPase activity and transport of rhodamine-6G (Fig. 2e).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataExpression of wild-type CKB1 in the ABC16 ckb1Δ strain restores beauvericin susceptibility, while expression of CKB1E220* maintains resistance.
“expression of wild-type CKB1 in the ABC16 ckb1Δ strain restored beauvericin susceptibility, while resistance was maintained upon expression of CKB1E220* (Fig. 3b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe interaction between beauvericin and rapamycin is abrogated by deletion of genes encoding FKBP12 and is impervious to deletion of PDR5.
“The interaction between beauvericin and rapamycin was abrogated by deletion of genes encoding FKBP12 (FPR1 in S. cerevisiae, RBP1 in C. albicans)25 and impervious to deletion of PDR5 (Supplementary Fig. 9), confirming the effects are mediated via TOR.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Cruz, M.C. et al. Rapamycin and less immunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR. Antimicrob. Agents Chemother. 45, 3162–3170 (2001). source
Not checked in the free run.
May combine two claims.
Findingown dataBeauvericin causes a significant reduction in Sch9 phosphorylation and a modest reduction in Ypk1 phosphorylation.
“Beauvericin caused a significant reduction in Sch9 phosphorylation and a modest reduction in Ypk1 phosphorylation (Fig. 4e, Supplementary Fig. 10).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataBeauvericin binds to Cka2 and Tor2.
“Thus, CK2 and TOR may be binding targets of beauvericin through which it exerts antifungal activity.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataBeauvericin enhances azole efficacy through inhibition of Pdr5, causing increased azole accumulation within the fungal cell.
“Thus, beauvericin enhances azole efficacy through inhibition of Pdr5, thereby causing increased azole accumulation within the fungal cell.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenqRT-PCR reactions were performed in triplicate for biological duplicate experiments.
“qRT-PCR reactions were performed in triplicate for biological duplicate experiments.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningBeauvericin activates CK2 by binding to Tor2 and inhibiting TORC1 function.
“Together, these results suggest that beauvericin activates CK2 by binding to Tor2 and inhibiting TORC1 function.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationInhibition of Hsp90 abrogates drug resistance in diverse human fungal pathogens, rendering resistant infections responsive to treatment.
“Inhibition of Hsp90 abrogates drug resistance in diverse human fungal pathogens, rendering resistant infections responsive to treatment7–9.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [7] Cowen, L.E. et al. Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. Proc. Natl. Acad. Sci. USA 106, 2818–2823 (2009). source
Not checked in the free run.
- cites [8] Robbins, N. et al. Hsp90 governs dispersion and drug resistance of fungal biofilms. PLoS Pathog. 7, e1002257 (2011). source
Not checked in the free run.
- cites [9] Cowen, L.E. & Lindquist, S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309, 2185–2189 (2005). source
Not checked in the free run.
May combine two claims.
PremisecitationBeauvericin was found to be well tolerated by human cells and to potentiate azole efficacy against Candida parapsilosis in a systemic infection model.
“it was found to be well tolerated by human cells and to potentiate azole efficacy against Candida parapsilosis in a systemic infection model by a mechanism that remains enigmatic12.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Zhang, L. et al. High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections. Proc. Natl. Acad. Sci. USA 104, 4606–4611 (2007). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe fluconazole resistance selection experiments were performed in biological duplicates.
“Experiments were performed in biological duplicates; plates were incubated at 30°C for five days and photographed each day.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo blinding was done in the murine model of disseminated candidiasis.
“No blinding was done.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenIn the radiolabelled fluconazole accumulation assay conditions, recovered cells were still in late log phase.
“In these conditions, recovered cells were still in late log phase.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationThe difference between the total and oligomycin-inhibited ATPase assays corresponds to the oligomycin-sensitive ATPase activity of Pdr5.
“The difference of both assays corresponds to the OM-sensitive ATPase activity of Pdr550.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [50] Ernst, R. et al. A mutation of the H-loop selectively affects rhodamine transport by the yeast multidrug ABC transporter Pdr5. Proc. Natl. Acad. Sci. USA 105, 5069–5074 (2008). source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone givenThe average coverage of each genome was sufficient for confident variant detection.
“The average coverage of each genome was sufficient for confident variant detection and is listed in Supplementary Table 3.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAP-MS was performed in three independent experiments.
“AP-MS was performed in three independent experiments.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCKB1 and CKB2 encode the non-redundant beta regulatory subunits of protein kinase CK2, which phosphorylates over 300 substrates, including Hsp90.
“CKB1 and CKB2 encode the non-redundant beta regulatory subunits of protein kinase CK2, which is an essential serine/threonine protein kinase that phosphorylates over 300 substrates, including Hsp9017.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Miyata, Y. Protein kinase CK2 in health and disease: CK2: the kinase controlling the Hsp90 chaperone machinery. Cell. Mol. Life Sci. 66, 1840–1849 (2009). source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationPdr5 transports a diverse set of structurally unrelated compounds including azoles, cycloheximide, and rhodamines.
“Pdr5 transports a diverse set of structurally unrelated compounds including azoles, cycloheximide, and rhodamines15.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Prasad, R. & Goffeau, A. Yeast ATP-binding cassette transporters conferring multidrug resistance. Annu. Rev. Microbiol. 66, 39–63 (2012). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll strains were assessed in biological triplicate experiments with technical duplicates.
“All strains were assessed in biological triplicate experiments with technical duplicates.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataNo growth defect was observed for cells plated on YEPD containing methanol compared to media without methanol.
“No growth defect was observed in comparison to media without methanol.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn S. cerevisiae and C. albicans, CK2 phosphorylates Hsp90, thereby modulating chaperone function.
“In S. cerevisiae and C. albicans, CK2 phosphorylates Hsp90, thereby modulating chaperone function27,28.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27] Mollapour, M. et al. Threonine 22 phosphorylation attenuates Hsp90 interaction with cochaperones and affects its chaperone activity. Mol. Cell 41, 672–681 (2011). source
Not checked in the free run.
- cites [28] Diezmann, S., Michaut, M., Shapiro, R.S., Bader, G.D. & Cowen, L.E. Mapping the Hsp90 genetic interaction network in Candida albicans reveals environmental contingency and rewired circuitry. PLoS Genet. 8, e1002562 (2012). source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationHsp90 regulates cellular responses required to survive drug-induced stress, and inhibition of Hsp90 transforms azoles from fungistatic to fungicidal.
“Hsp90 regulates cellular responses required to survive drug-induced stress, and inhibition of Hsp90 transforms azoles from fungistatic to fungicidal7,9.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [7] Cowen, L.E. et al. Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. Proc. Natl. Acad. Sci. USA 106, 2818–2823 (2009). source
Not checked in the free run.
- cites [9] Cowen, L.E. & Lindquist, S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309, 2185–2189 (2005). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe selection experiment with the ABC16 strain was performed once, while the selection experiment with the yor1Δ strain was done in biological triplicates.
“The selection experiment with the ABC16 strain was performed once, while the selection experiment with the yor1Δ strain was done in biological triplicates.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenControl experiments for AP-MS were performed in which the biotinylated-beauvericin was omitted.
“Control experiments were performed in which the biotinylated-beauvericin was omitted.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataMutations identified in CKB1, CKB2, and PDR5 were validated by Sanger sequencing.
“Mutations identified in CKB1, CKB2, and PDR5 were validated by Sanger sequencing.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHsp90 is an essential molecular chaperone that stabilizes diverse cellular regulators.
“Hsp90, an essential molecular chaperone that stabilizes diverse cellular regulators6.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Leach, M.D., Klipp, E., Cowen, L.E. & Brown, A.J.P. Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs. Nat. Rev. Microbiol. 10, 693–704 (2012). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenInfected mice were randomly chosen for each group.
“Infected mice were randomly chosen for each group.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSurvival data for all of the tested mice were included in the statistical analysis.
“Survival data for all of the tested mice were included in the statistical analysis.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The mechanism of beauvericin action (inhibition of Pdr5, TORC1, CK2, and Hsp90) identified in S. cerevisiae and C. albicans is conserved in other human fungal pathogens such as A. fumigatus and C. neoformans.
“potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens”
“Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for fungal infectious disease that evades resistance.”
The paper relies on this without support.
The therapeutic benefit of the beauvericin-fluconazole combination in mammalian infection models is mediated by the same dual targeting of multidrug efflux and TOR signaling.
“As a combination, there was potent therapeutic benefit of beauvericin and fluconazole (Fig. 6a).”
“Our findings reveal that dual targeting of multidrug efflux and TOR signaling provides a powerful strategy to enhance antifungal efficacy, impede drug resistance, and render resistant pathogens responsive to treatment.”
The paper relies on this without support.
The Pdr5 substitutions that enable beauvericin efflux and impair azole efflux are representative of resistance mechanisms that would emerge in clinical settings.
“Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux, thereby impeding resistance to the drug combination.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Beauvericin potentiates azole activity via both inhibition of TOR and multidrug efflux.
“The natural product beauvericin, which potentiates azole activity via both inhibition of TOR and multidrug efflux, is effective against diverse fungal pathogens including C. albicans, C. neoformans, and A. fumigatus87.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [87]
Beauvericin is effective against diverse fungal pathogens including C. albicans, C. neoformans, and A. fumigatus.
“The natural product beauvericin, which potentiates azole activity via both inhibition of TOR and multidrug efflux, is effective against diverse fungal pathogens including C. albicans, C. neoformans, and A. fumigatus87.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [87]
Combination therapy is an alternative approach to overcoming growing microbial infection resistance.
“Combination therapy is an alternative approach to overcoming the growing microbial infection resistance [23,24].”
From Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant <i>Candida auris</i> (2024) · cites this paper as [23]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
AP-MS buffer conditions counted inconsistently
MinorThe Results state that AP-MS used three distinct buffer conditions, but the Methods describe only two: experiments 1 and 2 used the same NP-40 buffer, while experiment 3 used Triton X-100 buffer.
“AP-MS was performed under three distinct buffer conditions with biological duplicates and negative controls.”
“Experiments 1 and 2 were performed using 0.1% NP-40 buffer, and experiment 3 was performed using 1% Triton X-100 buffer to allow for efficient extraction of membrane proteins.”
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- Authors
- Shekhar-Guturja, T., Gunaherath, G. M. K. B., Wijeratne, E. M. K., Lambert, J.-P., Averette, A. F., Lee, S. C., Kim, T., Bahn, Y.-S., Tripodi, F., Ammar, R., Döhl, K., Niewola-Staszkowska, K., Schmitt, L., Loewith, R. J., Roth, F. P., Sanglard, D., Andes, D., Nislow, C., Coccetti, P., Gingras, A.-C., Heitman, J., Gunatilaka, A. A. L., & Cowen, L. E.
- Affiliations
- University of Arizona (US)
- Mount Sinai Hospital (CA)
- Duke Medical Center (US)
- Yonsei University (KR)
- University of Milano-Bicocca (IT)
- University of Toronto (CA)
- Heinrich Heine University Düsseldorf (DE)
- University of Geneva (CH)
- Centre Hospitalier Universitaire Vaudois (CH)
- University of Wisconsin–Madison (US)
- University of British Columbia (CA)
- Corresponding author
- Cowen, Leah E
- ORCID
- Gunaherath, G M Kamal B
- Wijeratne, E M Kithsiri
- Lambert, Jean-Philippe
- Averette, Anna F
- Lee, Soo Chan
- Kim, Taeyup
- Bahn, Yong-Sun
- Tripodi, Farida
- Ammar, Ron
- Schmitt, Lutz
- Loewith, Robbie J
- Roth, Frederick P
- Sanglard, Dominique
- Andes, David
- Nislow, Corey
- Coccetti, Paola
- Gingras, Anne-Claude
- Heitman, Joseph
- Gunatilaka, A A Leslie
- Cowen, Leah E
- Venue
- Nature Chemical Biology
- Published
- 2016-08-29
- Volume
- 12
- Issue
- 10
- Pages
- 867-875
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5030160
- OpenAlex
- W2509038340
- Semantic Scholar
- 703e3c9f64b33ff7226b5d45e13b72dc9ef9243c
- Cited by
- 101
- References
- 57
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 11 · 2023: 9 · 2022: 15 · 2021: 8 · 2020: 13 · 2019: 10 · 2018: 9 · 2017: 9 · 2016: 2
- FWCI
- 9.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- SERVAL (Université de Lausanne) (acceptedVersion, other-oa)
- IRIS (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- TD Bank
- Genome Canada
- Ministry of Trade, Industry and Energy (N0001720)
- University of Toronto
- National Institutes of Health (5r01ai112595-04)
- Canadian Institutes of Health Research (119520_1, MOP-86452)
- Natural Sciences and Engineering Research Council of Canada (462167, 06261)
- National Cancer Institute (R01CA090265)
- National Institute of General Medical Sciences (P41GM094060)
- National Institute of Allergy and Infectious Diseases (R01-AI112595, P01AI104533, R56AI112595)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Keywords
- beauvericin, antifungal resistance, multidrug efflux, TOR signaling, casein kinase 2, HSP90 inhibition, invasive fungal infections, natural products, drug repurposing
- MeSH terms
- Antifungal Agents, Fungi, Microbial Sensitivity Tests, Mycoses, Signal Transduction, Drug Resistance, Multiple, ATP-Binding Cassette Transporters, HSP90 Heat-Shock Proteins, Drug Resistance, Fungal, Saccharomyces cerevisiae Proteins, Protein Kinase Inhibitors, Depsipeptides, Small Molecule Libraries, TOR Serine-Threonine Kinases
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