Aprepitant, an antiemetic agent, interferes with metal ion homeostasis of Candida auris and displays potent synergistic interactions with azole drugs
Open accessAbstract
With the rapid increase in the frequency of azole-resistant species, combination therapy appears to be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the effect of aprepitant, an antiemetic agent, on the antifungal activities of azole drugs against the multidrug-resistant Candida auris. Aprepitant reduced the minimum inhibitory concentration (MIC) of itraconazole in vitro, by up to eight-folds. Additionally, the aprepitant/itraconazole combination interfered significantly with the biofilm-forming ability of C. auris by 95 ± 0.13%, and significantly disrupted mature biofilms by 52 ± 0.83%, relative to the untreated control. In a Caenorhabditis elegans infection model, the aprepitant/itraconazole combination significantly prolonged the survival of infected nematodes by ~90% (five days post-infection) and reduced the fungal burden by ~92% relative to the untreated control. Further, this novel drug combination displayed broad-spectrum synergistic interactions against other medically important Candida species such as C. albicans, C. krusei, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 0.31). Comparative transcriptomic profiling and mechanistic studies indicated aprepitant/itraconazole interferes significantly with metal ion homeostasis and compromises the ROS detoxification ability of C. auris. This study presents aprepitant as a novel, potent, and broad-spectrum azole chemosensitizing agent that warrants further investigation.
AI snapshot
Written from the paper’s full text.
TL;DR
Aprepitant, an antiemetic agent, chemosensitizes multidrug-resistant *Candida auris* and other *Candida* species to azole drugs, especially itraconazole, producing fungicidal and antibiofilm activity. Its synergy appears mediated by interference with metal-ion homeostasis and ROS detoxification, with in vivo efficacy in a *C. elegans* infection model.
Key findings
- In checkerboard assays against ten *C. auris* isolates, aprepitant/itraconazole was synergistic against 8 isolates (ΣFICI 0.14–0.31) and additive against 2 (ΣFICI = 0.52); it re-sensitized all 3 isolates with reduced itraconazole susceptibility (MIC ≥1 µg/ml). Aprepitant also enhanced fluconazole (synergy in 4 isolates, additivity in 3) and voriconazole (synergy in 2, additivity in 6).
- The aprepitant/itraconazole combination inhibited *C. auris* biofilm formation by 95 ± 0.13% and reduced mature biofilm viability by 52 ± 0.83% relative to untreated control; neither agent alone interfered at the tested concentrations.
- In *C. elegans* infected with *C. auris* AR0390, the combination reduced fungal burden by ~92 ± 2.4% and improved 5-day survival to ~90%, versus 20% survival in untreated worms; itraconazole alone reduced burden by ~42 ± 3.6% and improved survival to ~40%.
- Broad-spectrum synergy with itraconazole occurred against *C. albicans*, *C. krusei*, *C. tropicalis*, and *C. parapsilosis* (ΣFICI 0.08–0.31), but was indifferent against *C. glabrata* (ΣFICI = 1.02). Transcriptomics identified 34 DEGs in the combination group (19 upregulated, 15 downregulated), including downregulated metal transporters *FTR1*, *ZRT2*, *CTR1* and upregulated ergosterol genes *ERG1*, *ERG2*, *ERG10*, *ERG24*; ROS levels increased ~600% versus untreated control.
Methods
- In vitro assays included standard broth microdilution checkerboard assays with aprepitant and azoles against *C. auris* isolates and other *Candida* species, time-kill assays, XTT biofilm assays, RNA-seq (NovaSeq6000; HISAT2, featureCounts, edgeR), RT-qPCR, ROS detection with carboxy-H2DCFDA, and iron-supplementation experiments.
- In vivo efficacy used *C. elegans* strain AU37 L4 worms infected with *C. auris* AR0390 and treated with DMSO, aprepitant (10 µg/ml), itraconazole (1 µg/ml), or the combination; outcomes were fungal CFU burden and Kaplan-Meier survival.
- Analysis defined synergy as ΣFICI ≤0.50, additivity as >0.50–≤1, and indifference as >1–≤4; DEGs required adjusted P <0.05 and >2-fold change; GO enrichment, one-way ANOVA with Dunnett’s test, and log-rank tests were used.
Limitations
- Stated by the paper: further molecular studies are needed to fully understand the mechanism of aprepitant’s azole chemosensitizing activity and its effect on the ergosterol pathway; efficacy in higher animal models and clinical studies is needed.
- Evident from the text: in vivo evidence is limited to a *C. elegans* infection model, with no mammalian infection model; the initial whole-cell screening data are unpublished; zinc supplementation could not be tested because zinc sulfate precipitated with aprepitant, and copper supplementation did not affect activity.
- Evident from the text: transcriptomic analysis used a strict significance threshold, aprepitant alone produced no significant transcriptome change, and *ERG11* upregulation did not meet significance, so parts of the mechanism remain inferred.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 35 cited sources checked · 0 supported · 0 flagged
- Findingown data
In a whole-cell screening study (unpublished data), aprepitant restored the antifungal activity of fluconazole against the test C. auris isolate.
“In a whole-cell screening study aimed at identifying novel azole chemosensitizing agents (unpublished data), we noticed that the antiemetic agent aprepitant was able to restore the antifungal activity of fluconazole against the test C. auris isolate.”
Quote in the paperSubstantial claim - Findingown data
Aprepitant re-sensitized all tested C. auris isolates (n=3) with reduced susceptibility to itraconazole (MIC ≥1 μg/ml).
“Importantly, aprepitant was able to re-sensitize all tested isolates (n = 3) that displayed reduced susceptibility to itraconazole (MIC ≥1 µg/ml).”
Quote in the paperSubstantial claim - Findingown data
In a C. elegans infection model, the aprepitant/itraconazole combination significantly prolonged the survival of infected nematodes by ~90% at five days post-infection relative to untreated control.
“In a Caenorhabditis elegans infection model, the aprepitant/itraconazole combination significantly prolonged the survival of infected nematodes by ~90% (five days post-infection)”
Quote in the paperSubstantial claim - Findingown data
Single treatments with either aprepitant or itraconazole at respective concentrations failed to interfere with the biofilm-forming ability of C. auris AR0390.
“However, single treatments with either aprepitant or itraconazole at the respective concentrations failed to interfere with the biofilm-forming ability of the test isolate.”
Quote in the paperSubstantial claim - Findingown data
Genes involved in ergosterol synthesis (ERG1, ERG2, ERG10, ERG24), stress responses (DDR48 and RTA3), and drug transporters (CDR1, MDR1, DUR3) were upregulated in the aprepitant/itraconazole treated sample.
“Genes involved in ergosterol synthesis (ERG1, ERG2, ERG10, ERG24), stress responses (DDR48 and RTA3), and drug transporters (CDR1, MDR1, DUR3) were upregulated in the aprepitant/itraconazole treated sample.”
Quote in the paperSubstantial claim
- Findingown data
The combination of aprepitant and itraconazole displayed fungicidal activity against C. auris AR0390, generating ~3-log10 reduction in CFU count over 24 hours.
“the combination of aprepitant and itraconazole (at the same concentrations each drug was tested alone) displayed fungicidal activity against the test isolate generating ~ 3-log10 reduction in the CFU count over 24 hours.”
Quote in the paperSubstantial claim - Findingown data
The aprepitant/itraconazole combination significantly reduced the viability of C. auris AR0390 cells in mature biofilms by 52 ± 0.83%.
“the aprepitant/itraconazole combination, at the same concentrations, was able to significantly reduce the viability of C. auris AR0390 cells present in mature biofilms by 52 ± 0.83%”
Quote in the paperSubstantial claim - Findingown data
In a C. elegans infection model, the aprepitant/itraconazole combination reduced the fungal burden by ~92% relative to untreated control.
“and reduced the fungal burden by ~92% relative to the untreated control.”
Quote in the paperSubstantial claim - Findingown data
Neither aprepitant nor itraconazole alone at respective concentrations interfered with the viability of C. auris cells within mature biofilms.
“As expected, neither aprepitant nor itraconazole alone, at the respective concentrations, was able to interfere with the viability of C. auris cells within mature biofilms.”
Quote in the paperSubstantial claim - Findingown data
The combination of aprepitant (10 μg/ml) and itraconazole (1 μg/ml) significantly inhibited the biofilm-forming ability of C. auris AR0390 by ~95 ± 0.13% compared to untreated control.
“the combination of aprepitant (at 10 µg/ml) and itraconazole (at 1 µg/ml) significantly inhibited the biofilm-forming ability of the test isolate by ~95 ± 0.13% compared to the untreated control.”
Quote in the paperSubstantial claim - Findingown data
Aprepitant restored fluconazole susceptibility only in two fluconazole-resistant C. auris isolates, AR0388 and AR0390.
“aprepitant was able to restore the fluconazole susceptibility only in two fluconazole-resistant isolates, AR0388, and AR0390.”
Quote in the paperSubstantial claim - Findingown data
Aprepitant reduced the minimum inhibitory concentration (MIC) of itraconazole in vitro by up to eight-fold against C. auris.
“Aprepitant reduced the minimum inhibitory concentration (MIC) of itraconazole in vitro, by up to eight-folds.”
Quote in the paperSubstantial claim - Findingown data
Aprepitant failed to re-sensitize any tested voriconazole-resistant C. auris isolates (n=3) with MIC ≥1 μg/ml.
“However, aprepitant failed to re-sensitize any of the tested voriconazole-resistant isolates (n = 3) that exhibited MIC ≥1 µg/ml.”
Quote in the paperSubstantial claim - Findingown data
The aprepitant/itraconazole combination significantly disrupted mature C. auris biofilms by 52 ± 0.83% relative to untreated control.
“significantly disrupted mature biofilms by 52 ± 0.83%, relative to the untreated control.”
- Also stated in: § Effect of aprepitant/itraconazole against C. auris biofilms · plain
“the aprepitant/itraconazole combination, at the same concentrations, was able to significantly reduce the viability of C. auris AR0390 cells present in mature biofilms by 52 ± 0.83%”
Quote in the paperSubstantial claim - Also stated in: § Effect of aprepitant/itraconazole against C. auris biofilms · plain
- Findingown data
Aprepitant alone at 10 μg/ml did not produce observable antifungal activity against C. auris AR0390.
“aprepitant (at 10 µg/ml), by itself, did not produce any observable antifungal activity against the test isolate (AR0390).”
Quote in the paperSubstantial claim - Findingown data
The aprepitant/itraconazole combination significantly inhibited the biofilm-forming ability of C. auris by 95 ± 0.13% relative to untreated control.
“the aprepitant/itraconazole combination interfered significantly with the biofilm-forming ability of C. auris by 95 ± 0.13%”
- Also stated in: § Effect of aprepitant/itraconazole against C. auris biofilms · plain
“the combination of aprepitant (at 10 µg/ml) and itraconazole (at 1 µg/ml) significantly inhibited the biofilm-forming ability of the test isolate by ~95 ± 0.13% compared to the untreated control.”
Quote in the paperSubstantial claim - Also stated in: § Effect of aprepitant/itraconazole against C. auris biofilms · plain
- Findingown data
The initial screen identified aprepitant as a potent hit compound that restored the antifungal activity of fluconazole against the multidrug-resistant strain C. albicans AR0390.
“Our initial screen identified aprepitant (an antiemetic agent) as a potent hit compound that restored the antifungal activity of fluconazole against the multidrug-resistant strain C. albicans AR0390.”
Quote in the paperSubstantial claim - Findingown data
A total of 34 DEGs (19 upregulated + 15 downregulated) were identified in the aprepitant/itraconazole treated sample.
“a total of 34 DEGs (19 upregulated + 15 downregulated) were identified in the aprepitant/itraconazole treated sample”
Quote in the paperSubstantial claim - Findingown data
RT-qPCR confirmed significant downregulation of metal transport-related genes FTR1, ZRT2, and CTR1 only in cells treated with the aprepitant/itraconazole combination.
“confirmed the significant overexpression of ergosterol biosynthesis-related genes (ERG1, ERG2, ERG10) and the significant downregulation of metal transport-related genes (FTR1, ZRT2, and CTR1) only in the cells treated with the aprepitant/itraconazole combination”
Quote in the paperSubstantial claim - Findingown data
Neither aprepitant nor itraconazole alone was able to interfere with the biofilm-forming ability of C. auris.
“While neither aprepitant nor itraconazole alone was able to interfere with the biofilm-forming ability of C. auris”
Quote in the paperSubstantial claim - Findingown data
When the assay medium was supplemented with iron, C. auris cells generated significantly lower levels of ROS compared to iron-deficient media.
“when the assay medium was supplemented with iron, we noticed that C. auris cells generated significantly lower levels of ROS as compared to iron-deficient media”
Quote in the paperSubstantial claim - Findingown data
A total of 25 GO terms were downregulated in the aprepitant/itraconazole treated sample.
“However, a total of 25 GO terms were found to be downregulated in the aprepitant/itraconazole treated sample”
Quote in the paperSubstantial claim - Findingown data
The aprepitant/itraconazole combination was effective at reducing the metabolic activity of fungal cells residing within premature and mature biofilms.
“the aprepitant/itraconazole combination was effective at reducing the metabolic activity of fungal cells residing within premature and mature biofilms.”
Quote in the paperSubstantial claim - Findingown data
Itraconazole at 1 μg/ml significantly increased ROS levels by 270% relative to the untreated control.
“itraconazole treatment (at 1 µg/ml) significantly increased the ROS levels by 270% relative to the untreated control”
Quote in the paperSubstantial claim - Findingown data
Among the enriched GO terms, only one GO term related to membrane components was upregulated in the aprepitant/itraconazole sample.
“Among the enriched GO terms, only one GO term related to membrane components was upregulated in the aprepitant/itraconazole sample”
Quote in the paperNot a substantial claim - Findingown data
The aprepitant/itraconazole combination generated ~15 times more ROS levels compared to the untreated control.
“This effect was even more pronounced with the aprepitant/itraconazole combination which generated ~ 15-times more ROS levels, compared to the untreated control.”
Quote in the paperSubstantial claim - Findingown data
Aprepitant at 10 μg/ml did not improve the survival of infected nematodes with respect to the untreated control.
“aprepitant at 10 µg/ml did not improve the survival of infected nematodes with respect to the untreated control.”
Quote in the paperNot a substantial claim - Findingown data
A total of 18 DEGs (10 upregulated + 8 downregulated) were detected in samples treated with itraconazole alone.
“a total of 18 DEGs (10 upregulated + 8 downregulated) were detected in samples treated with itraconazole alone”
Quote in the paperNot a substantial claim - Findingown data
Iron supplementation negated the fungicidal activity of aprepitant/itraconazole as shown in time-kill kinetics.
“iron supplementation negated the fungicidal activity of aprepitant/itraconazole as shown in our time-kill kinetics.”
Quote in the paperSubstantial claim - Findingown data
Several genes involved in ergosterol biosynthesis were significantly upregulated, such as ERG1, ERG2, and ERG10.
“we noticed that several genes involved in ergosterol biosynthesis were significantly upregulated such as ERG1, ERG2, and ERG10.”
Quote in the paperNot a substantial claim - Findingown data
Aprepitant alone at 10 μg/ml failed to reduce the fungal CFU burden in C. elegans nematodes infected with C. auris AR0390.
“treatment with aprepitant alone at 10 µg/ml failed to reduce the fungal CFU burden in C. elegans nematodes infected with C. auris AR0390.”
Quote in the paperSubstantial claim - Findingown data
In iron-supplemented media, C. auris cells treated with aprepitant/itraconazole produced significantly lower ROS levels compared to iron-depleted media.
“in iron supplemented media, C. auris cells treated with aprepitant/itraconazole produced significantly lower ROS levels, compared to iron-depleted media.”
Quote in the paperSubstantial claim - Findingown data
Among upregulated genes in the itraconazole treated condition were amino acid permeases (DIP5 and CAN1), stress-associated genes (DDR48 and PGA31), ergosterol biosynthesis (ERG24), and a redox related gene, ferric reductase (FRE3).
“Among the upregulated genes in the itraconazole treated condition were amino acid permeases (DIP5 and CAN1), stress-associated genes (DDR48 and PGA31), ergosterol biosynthesis (ERG24), and a redox related gene, ferric reductase (FRE3).”
Quote in the paperNot a substantial claim - Findingown data
Itraconazole at 1 μg/ml (1 × MIC) enhanced the survival of infected worms by ~40% (P < 0.05), compared to only 20% in the untreated group.
“itraconazole at 1 µg/ml (1 × MIC) enhanced the survival of the infected worms by ~ 40% (P < 0.05), compared to only 20% in the untreated group.”
Quote in the paperSubstantial claim - Findingown data
Copper supplementation did not affect the antifungal activity of aprepitant/itraconazole.
“copper supplementation did not affect the antifungal activity of aprepitant/itraconazole (data not shown).”
Quote in the paperSubstantial claim - Findingown data
Aprepitant by itself compromised the ROS detoxification ability of C. auris, resulting in elevated ROS levels eight times higher than the untreated control.
“aprepitant by itself compromised the ROS detoxification ability of C. auris, resulting in elevated ROS levels (eight-times higher compared to the untreated control).”
Quote in the paperSubstantial claim - Findingown data
Aprepitant at the tested concentration has no significant effect on the C. auris transcriptome.
“Our data indicate that aprepitant, at the tested concentration, has no significant effect on C. auris’ transcriptome.”
Quote in the paperSubstantial claim - Findingown data
The iron-regulated 1,3-beta glucan-linked cell wall gene (PIR1) and the vacuolar calcium P-type ATPase (PMC1) were among the upregulated DEGs in the aprepitant/itraconazole treated sample.
“Additionally, the iron-regulated 1,3-beta glucan-linked cell wall gene (PIR1) and the vacuolar calcium P-type ATPase (PMC1) were also among the upregulated DEGs.”
Quote in the paperNot a substantial claim - Findingown data
No significant overrepresented GO terms were found in the itraconazole treated condition.
“However, no significant overrepresented GO terms were found in the itraconazole treated condition.”
Quote in the paperSubstantial claim - Findingown data
The aprepitant/itraconazole combination increased ROS production by ~600% relative to the untreated control.
“the aprepitant/itraconazole combination resulted in a more prominent effect by increasing the ROS production by ~ 600% relative to the untreated control”
Quote in the paperSubstantial claim - Findingown data
Of the downregulated GO terms, 18 were associated with membrane transport processes.
“Notably, 18 downregulated GO terms were found to be associated with membrane transport processes”
Quote in the paperSubstantial claim - Findingown data
Itraconazole at 1 μg/ml (1 × MIC) significantly reduced the fungal CFU burden by ~42 ± 3.6% compared to the untreated control.
“itraconazole at 1 µg/ml (1 × MIC) was able to significantly reduce the fungal CFU burden by ~42 ± 3.6%, compared to the untreated control.”
Quote in the paperSubstantial claim - Findingown data
Iron supplementation interfered significantly with the synergistic relationship of aprepitant and itraconazole, as demonstrated by a time-kill assay.
“iron supplementation interfered significantly with the synergistic relationship of aprepitant and itraconazole, as demonstrated by a time-kill assay.”
Quote in the paperSubstantial claim - Findingown data
The aprepitant/itraconazole combination significantly reduced the C. auris CFU burden in infected nematodes by ~92 ± 2.4% compared to the untreated control.
“the aprepitant/itraconazole combination was able to significantly reduce the C. auris CFU burden in the infected nematodes by ~92 ± 2.4%, compared to the untreated control.”
Quote in the paperSubstantial claim - Findingown data
RT-qPCR confirmed significant overexpression of ergosterol biosynthesis-related genes ERG1, ERG2, and ERG10 only in cells treated with the aprepitant/itraconazole combination.
“confirmed the significant overexpression of ergosterol biosynthesis-related genes (ERG1, ERG2, ERG10) and the significant downregulation of metal transport-related genes (FTR1, ZRT2, and CTR1) only in the cells treated with the aprepitant/itraconazole combination”
Quote in the paperSubstantial claim - Findingown data
No significant change in C. auris transcriptome was observed in the aprepitant treated condition.
“no significant change in C. auris’ transcriptome was observed in the aprepitant treated condition”
Quote in the paperNot a substantial claim - Findingown data
Of those downregulated GO terms, 11 were involved in metal ions and cation transport.
“of which 11 GO terms were involved in metal ions and cation transport”
Quote in the paperSubstantial claim - Findingown data
Only 20% of untreated C. elegans nematodes survived C. auris infection for five days post-infection.
“only 20% of the untreated C. elegans nematodes survived C. auris infection for five days post-infection.”
Quote in the paperSubstantial claim - Findingown data
Several high-affinity glucose transporters (HGT6, HGT8, HGT12) were among the downregulated DEGs in the aprepitant/itraconazole treated sample.
“Also, several high-affinity glucose transporters (HGT6, HGT8, HGT12) were among the downregulated DEGs in the aprepitant/itraconazole treated sample.”
Quote in the paperNot a substantial claim - Findingown data
Even in the presence of iron, the aprepitant/itraconazole combination was still able to exert a noticeable fungistatic activity against C. auris.
“even in the presence of iron, the aprepitant/itraconazole combination was still able to exert a noticeable fungistatic activity against C. auris.”
Quote in the paperSubstantial claim - Findingown data
Aprepitant interacted synergistically with itraconazole against the majority of Candida isolates tested.
“aprepitant interacted synergistically with itraconazole against the majority of Candida isolates tested.”
Quote in the paperSubstantial claim - Findingown data
In C. auris AR0390 treated with aprepitant/itraconazole, 26 GO terms were significantly overrepresented (enriched).
“Twenty-six GO terms were significantly overrepresented (enriched) in the aprepitant/itraconazole treated condition.”
Quote in the paperSubstantial claim - Findingown data
Ferrous sulfate at 50 μM completely negated the fungicidal activity of the aprepitant/itraconazole combination against C. auris AR0390.
“Ferrous sulfate (at 50 µM) completely negated the fungicidal activity of the aprepitant/itraconazole combination against the test isolate (C. auris AR0390).”
Quote in the paperSubstantial claim - Findingown data
Aprepitant at 10 μg/ml significantly increased intracellular ROS levels by ~300% relative to the untreated control.
“aprepitant (at 10 µg/ml) significantly increased the intracellular ROS levels by ~ 300% relative to the untreated control”
Quote in the paperSubstantial claim - Findingown data
Several genes involved in metal ion transport were significantly downregulated in cells treated with aprepitant/itraconazole, relative to the untreated control.
“several genes involved in metal ions transport were significantly downregulated in cells treated with aprepitant/itraconazole, relative to the untreated control.”
Quote in the paperSubstantial claim - Findingown data
The aprepitant/itraconazole combination significantly enhanced the survival of infected nematodes, with ~90% (P < 0.05) of C. elegans remaining alive for five days.
“the aprepitant/itraconazole combination significantly enhanced the survival of the infected nematodes as ~ 90% (P < 0.05) of C. elegans remained alive for five days.”
Quote in the paperSubstantial claim - Findingown data
In contrast to iron, copper supplementation did not interfere with the antifungal activity of the aprepitant/itraconazole combination.
“in contrast to iron, copper supplementation did not interfere with the antifungal activity of the aprepitant/itraconazole combination.”
Quote in the paperNot a substantial claim - Findingown data
Screening data revealed that aprepitant was able to restore the antifungal activity of fluconazole against the test isolate.
“The screening data (unpublished) revealed aprepitant, an NK1 antagonist used for the treatment of chemotherapy-associated emesis, was able to restore the antifungal activity of fluconazole against the test isolate.”
Quote in the paperSubstantial claim - Findingown data
Checkerboard data indicate that aprepitant enhances the antifungal activity of azole drugs against various Candida species.
“Checkerboard data indicate that aprepitant enhances the antifungal activity of azole drugs against various Candida species.”
Quote in the paperSubstantial claim - Premisecitation
Resistance to major antifungal agents, including first-line therapeutics, is common among C. auris isolates.
“Unfortunately, resistance to major antifungal agents, including to the first-line therapeutics, was reported to be common among C. auris isolates [4].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] source
Not checked in the free run.
- Interpretationown data
Aprepitant/itraconazole compromises the ROS detoxification ability of C. auris.
“Comparative transcriptomic profiling and mechanistic studies indicated aprepitant/itraconazole interferes significantly with metal ion homeostasis and compromises the ROS detoxification ability of C. auris.”
Quote in the paperSubstantial claim - Interpretationown data
The aprepitant/itraconazole combination has potent ability to interfere with both early and late phases of C. auris biofilms.
“These data indicate the potent ability of aprepitant/itraconazole to interfere with both the early and late phases of C. auris biofilms.”
Quote in the paperSubstantial claim - Interpretationown data
Aprepitant/itraconazole interferes significantly with metal ion homeostasis of C. auris.
“Comparative transcriptomic profiling and mechanistic studies indicated aprepitant/itraconazole interferes significantly with metal ion homeostasis and compromises the ROS detoxification ability of C. auris.”
Quote in the paperSubstantial claim- Rests on an assumption: Changes in expression of metal ion transport genes (FTR1, ZTR2, CTR1) reflect interference with metal ion homeostasis in C. auris.
- Premisecitation
Disturbance in iron transport was reported to affect membrane permeability and enhance the activity of drugs that target cell membrane biosynthetic pathways such as azoles.
“Disturbance in iron transport was reported to affect the membrane permeability and enhance the activity of drugs that target cell membrane biosynthetic pathways such as azoles [67].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [67] source
Not checked in the free run.
- Interpretationown data
The synergistic relationship between aprepitant and itraconazole appears to be mediated through potent interference with metal ion homeostasis and subsequent compromise in ROS detoxifying mechanisms and ergosterol biosynthesis.
“The synergistic relationship between aprepitant and itraconazole appears to be mediated through potent interference with metal ion homeostasis, and the subsequent compromise in ROS detoxifying mechanisms and ergosterol biosynthesis”
Quote in the paperSubstantial claim - Interpretationown data
Aprepitant/itraconazole has potent in vivo efficacy for treating C. auris infection of C. elegans.
“Altogether, these findings indicate that aprepitant/itraconazole has a potent in vivo efficacy of treating C. auris infection of C. elegans”
Quote in the paperSubstantial claim - Interpretationown data
Other additional mechanisms may contribute to the synergistic relationship between aprepitant and itraconazole.
“This suggests that other additional mechanisms may contribute to the synergistic relationship between aprepitant and itraconazole.”
Quote in the paperSubstantial claim - Interpretationown data
The aprepitant/itraconazole combination has a negative impact on ion homeostasis in C. auris.
“indicating the negative impact that aprepitant/itraconazole combination has on the ions homeostasis in C. auris.”
Quote in the paperSubstantial claim - Interpretationown data
The aprepitant/itraconazole combination demonstrated potent in vivo efficacy in a C. elegans infection model.
“this novel drug combination demonstrated potent in vivo efficacy in a C. elegans infection model.”
Quote in the paperSubstantial claim - Interpretationown data
The aprepitant/itraconazole combination can interfere with metal ion homeostasis in C. auris.
“This observation suggests the aprepitant/itraconazole combination can interfere with metal ion homeostasis in C. auris.”
Quote in the paperSubstantial claim - Interpretationown data
Aprepitant was able to enhance the antifungal activity of azole drugs, particularly itraconazole.
“our data indicate that aprepitant was able to enhance the antifungal activity of azole drugs, particularly itraconazole.”
Quote in the paperSubstantial claim - Interpretationcitation
Increases in ROS levels could explain the observed fungicidal activity against planktonic and biofilm C. auris.
“These increases in ROS levels could explain the observed fungicidal activity against planktonic and biofilms of C. auris as previously demonstrated in other studies [57–59].”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
Interference with iron homeostasis is a key mechanism that contributes to the synergistic relationship observed between aprepitant and itraconazole against C. auris.
“with iron homeostasis is a key mechanism that contributes to the synergistic relationship observed between aprepitant and itraconazole against C. auris.”
Quote in the paperSubstantial claim - Premisecitation
Metal ions, particularly iron, play a critical role in the activity of many enzymes involved in the detoxification of reactive oxygen species.
“One striking example is the critical role of metal ions, particularly iron, in the activity of many enzymes involved in the detoxification of reactive oxygen species (ROS) [54–56].”
Quote in the paperSubstantial claim0 of 3 sources checked
- May combine two claims. 21
- Classified as probably not a substantial claim. 19
May combine two claims.
Findingown dataThe aprepitant/itraconazole combination inhibited visual growth of C. albicans TWO7243, C. krusei ATCC 14243, C. tropicalis ATCC 1369, and C. parapsilosis ATCC 22019, and reduced CFU counts by ~2-4 orders of magnitude relative to untreated control.
“the aprepitant/itraconazole combination inhibited the visual growth of C. albicans (TWO7243), C. krusei (ATCC 14243), C. tropicalis (ATCC 1369), and C. parapsilosis (ATCC 22019), and reduced the CFU counts by ~ 2–4 orders of magnitude relative to the untreated control”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAprepitant enhanced the antifungal activity of itraconazole against all ten tested C. auris isolates, with a synergistic relationship against eight isolates (ΣFICI 0.14-0.31) and an additive relationship against two isolates (ΣFICI=0.52).
“when combined with itraconazole, aprepitant was able to enhance the antifungal activity of itraconazole against all ten tested isolates, resulting in a synergistic relationship observed against eight isolates (ƩFICI ranged from 0.14 to 0.31) and an additive relationship observed against two isolates (ƩFICI = 0.52).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataItraconazole at 1×MIC (1 μg/ml) exhibited fungistatic activity for 12 h post-incubation, with rapid fungal re-growth thereafter.
“Itraconazole, at 1 × MIC (1 µg/ml), exhibited fungistatic activity for 12 h post-incubation; however, rapid fungal re-growth was observed thereafter.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe aprepitant/itraconazole combination displayed broad-spectrum synergistic interactions against other medically important Candida species (C. albicans, C. krusei, C. tropicalis, C. parapsilosis; ΣFICI 0.08-0.31), except C. glabrata where an indifferent effect was observed (ΣFICI=1.02).
“this novel drug combination displayed broad-spectrum synergistic interactions against other medically important Candida species such as C. albicans, C. krusei, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 0.31).”
- Also stated in: § Effect of aprepitant/itraconazole against other Candida species · plain
“aprepitant exerted a synergistic relationship with itraconazole (ƩFICI ranged from 0.08 to 0.31) against all isolates, except for C. glabrata isolates where an indifferent effect was observed (ƩFICI = 1.02).”
Quote in the paperSubstantial claim- Also stated in: § Effect of aprepitant/itraconazole against other Candida species · plain
May combine two claims.
Findingown dataAprepitant exerted a synergistic relationship with itraconazole (ΣFICI 0.08-0.31) against all tested Candida isolates except C. glabrata, where an indifferent effect was observed (ΣFICI=1.02).
“aprepitant exerted a synergistic relationship with itraconazole (ƩFICI ranged from 0.08 to 0.31) against all isolates, except for C. glabrata isolates where an indifferent effect was observed (ƩFICI = 1.02).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAprepitant enhanced the antifungal activity of fluconazole against seven C. auris isolates, with a synergistic relationship against four isolates (ΣFICI 0.09-0.50) and an additive relationship against three isolates (ΣFICI 0.51-0.63).
“aprepitant was able to enhance the antifungal activity of fluconazole against seven isolates with a synergistic relationship observed against four isolates (ƩFICI ranged from 0.09 to 0.50) and an additive relationship observed against three isolates (ƩFICI ranged from 0.51 to 0.63).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA total of 18 and 34 genes displayed significant changes in expression in groups treated with itraconazole and aprepitant/itraconazole, respectively, compared to the untreated control.
“a total of 18 and 34 genes displayed significant changes in expression in groups treated with itraconazole and aprepitant/itraconazole respectively, compared to the untreated control.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCombining aprepitant with itraconazole changed the fungistatic nature of itraconazole and produced a prominent fungicidal effect against C. auris AR0390 as demonstrated by the time-kill study.
“changed the fungistatic nature of itraconazole and produced a prominent fungicidal effect against C. auris AR0390 as demonstrated by the time-kill study.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIron supplementation restored visible growth of C. auris colonies on YPD agar and eliminated the fungicidal effect of the aprepitant/itraconazole combination in a spotting assay.
“iron supplementation restored the visible growth of C. auris colonies on YPD agar and eliminated the fungicidal effect of the aprepitant/itraconazole combination”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe data show increased mRNA levels of ERG11, but this upregulation did not meet the strict criteria for statistical significance.
“Our data also shows increased mRNA levels of ERG11, however, this upregulation didn’t meet our strict criteria for statistical significance.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataA total of 81.9 million reads were obtained with over 95% mapping rates across all samples.
“A total of 81.9 million reads were obtained with over 95% mapping rates observed across all samples.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAll RNAs used for downstream experiments had RNA integrity numbers (RIN) of 9.5 and above.
“The RNA quality was checked on a bioanalyzer Nano chip (Agilent) and all RNAs used for downstream experiments were determined to have RNA integrity numbers (RIN) of 9.5 and above.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDrug combinations have been utilized efficiently to treat various bacterial and viral infections and cancer.
“Historically, drug combinations have been utilized efficiently to treat various bacterial and viral infections and to fight cancer [18–21].”
Quote in the paperNot a substantial claim0 of 4 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAccording to CDC, 90% of C. auris isolates are resistant to fluconazole and around 30% are resistant to amphotericin B.
“According to the CDC, 90% of C. auris isolates are resistant to the antifungal activity of fluconazole and around 30% of isolates are resistant to amphotericin B [5].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [5] CDC. Antifungal susceptibility and resistance breakpoints in Candida auris; 2020. (Accessed on 18 April 2020). Available from: https://www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOverexpression or mutation of ERG11, and upregulation of ABC and MFS efflux transporters, are major triggers of azole resistance in Candida species.
“Overexpression or mutation of ERG11, in addition to the upregulation of ABC and MFS efflux transporters, are known to be major triggers of azole resistance in Candida species [17].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Whaley SG, 2016, Front Microbiol
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationC. auris is an emerging fungal pathogen implicated in numerous global outbreaks of life-threatening candidemia, leading to significant morbidity and high mortality.
“Candida auris is an emerging fungal pathogen that has been recently implicated in numerous global outbreaks of life-threatening candidemia, leading to significant morbidity and high rates of mortality [1,2].”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAzole drugs target ergosterol biosynthesis through inhibition of lanosterol 14 alpha methyltransferase (Erg11p), resulting in depletion of ergosterol and accumulation of cytotoxic metabolites.
“Azole drugs target ergosterol biosynthesis through the inhibition of lanosterol 14 alpha methyltransferase (Erg11p) resulting in depletion of the vital cell membrane component, ergosterol, and accumulation of cytotoxic metabolites [10].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationOnly three classes of systemic antifungal drugs (azoles, polyenes, echinocandins) are available for treatment of invasive Candida infections.
“Currently, only three classes of systemic antifungal drugs (azoles, polyenes, and echinocandins) are available for the treatment of invasive Candida infections [9].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] source
Not checked in the free run.
May combine two claims.
Interpretationown dataAprepitant is a novel, potent, and broad-spectrum azole chemosensitizing agent.
“This study presents aprepitant as a novel, potent, and broad-spectrum azole chemosensitizing agent”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataBecause all genes differentially expressed in response to aprepitant/itraconazole treatments have orthologs in other Candida species, the combination is expected to have a similar mechanism of action in all susceptible species.
“Of note, since all genes that demonstrated differential expression in response to aprepitant/itraconazole treatments have orthologs in other Candida species, we expect this combination would have a similar mechanism of action in all susceptible species.”
Quote in the paperNot a substantial claim- Rests on an assumption: All genes that demonstrated differential expression in response to aprepitant/itraconazole treatments have orthologs in other Candida species.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIron homeostasis has been regarded as a potential target for other azole chemosensitizing agents such as doxycycline and lactoferrin.
“Notably, iron homeostasis has been regarded as a potential target for other azole chemosensitizing agents such as doxycycline and lactoferrin [65,66].”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationIron depletion is thought to suppress the calcineurin pathway, leading to impairment of drug-induced stress responses in Candida.
“Additionally, iron depletion is thought to suppress the calcineurin pathway, leading to impairment of drug-induced stress responses in Candida [68].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [68] source
Not checked in the free run.
May combine two claims.
Interpretationown dataBoth aprepitant and the aprepitant/itraconazole combination can interfere significantly with ROS detoxification in C. auris, apparently through interference with metal ion transport.
“This result indicates that both aprepitant and the aprepitant/itraconazole combination can interfere significantly with ROS detoxification in C. auris, apparently through the interference with metal ion transport.”
Quote in the paperSubstantial claim- Rests on an assumption: Metal ion homeostasis is critical for multiple biological processes, including redox regulatory mechanisms.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationBiofilms are known to hinder the penetration of antifungal drugs and host immune effectors and also trigger the formation of Candida persister cells, leading to poor clinical outcomes.
“biofilms are known to hinder the penetration of antifungal drugs and host immune effectors and also trigger the formation of Candida persister cells, leading to poor clinical outcomes [52,53].”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationA well-documented virulence factor of Candida species is the notable ability to form adherent structures, known as biofilms, on surfaces of medical devices.
“A well-documented virulence factor of Candida species is the notable ability to form adherent structures, known as biofilms, on surfaces of medical devices [49–51].”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataIt was not possible to examine the effect of zinc supplementation on the relationship between aprepitant and itraconazole because zinc sulfate mixed with aprepitant caused an immediate precipitation reaction.
“it was not possible to examine the effect of zinc supplementation on the relationship between aprepitant and itraconazole, as we noticed an immediate precipitation reaction when zinc sulfate was mixed with aprepitant.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSimilar observations have been recorded in plant and mammalian cells, where high ROS levels were produced in iron-depleting conditions, indicating that iron homeostasis has a conservative protective role against ROS formation.
“similar observations have been recorded in plant and mammalian cells whereas high ROS levels were produced in iron depleting conditions [60,61], indicating that iron homeostasis has a conservative protective role against the ROS formation.”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevious studies have shown that ergosterol depletion causes the upregulation of several genes involved in ergosterol biosynthesis.
“Indeed, previous studies have shown that ergosterol depletion causes the upregulation of several genes involved in ergosterol biosynthesis [63,64].”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataThe upregulation of ERG genes could be viewed as a compensatory mechanism by which C. auris cells try to adapt to reduced ergosterol content.
“This upregulation of ERG genes could be viewed as a compensatory mechanism by which C. auris cells try to adapt to the reduced ergosterol content.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn Saccharomyces cerevisiae, iron homeostasis is known to be an important regulator of ergosterol biosynthesis.
“In Saccharomyces cerevisiae, iron homeostasis is known to be an important regulator of ergosterol biosynthesis [62].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [62] source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe aprepitant/itraconazole combination displayed broad-spectrum antifungal activity and was fungicidal against planktonic and biofilm C. auris.
“The aprepitant/itraconazole combination displayed broad-spectrum antifungal activity and was fungicidal against planktonic and biofilms of C. auris”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn iron-depleting conditions, yeast cells were reported to express higher mRNA levels of several ERG genes such as ERG1, ERG7, and ERG11.
“In iron depleting conditions, yeast cells were reported to express higher mRNA levels of several ERG genes such as ERG1, ERG7, and ERG11 [62].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [62] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationC. auris has been classified by the CDC as an urgent threat that requires immediate action.
“The risk posed by the recently identified fungal pathogen C. auris has prompted CDC to classify C. auris as an urgent threat that requires immediate action [3].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] CDC. Antibiotic resistance threats in the United States. Atlanta (GA): U.S. Department of Health and Human Services, Antibiotic Resistance Threats in the United States; 2019. (Accessed on 18 April 2020). Available from: https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationFungicidal therapeutics are expected to improve the clinical outcome of invasive Candida infections, especially in patients with compromised immune systems.
“fungicidal therapeutics are expected to improve the clinical outcome of invasive Candida infections, especially in patients with compromised immune systems [47,48].”
Quote in the paperSubstantial claim0 of 2 sources checked
The paper relies on this without support.
Changes in expression of metal ion transport genes (FTR1, ZTR2, CTR1) reflect interference with metal ion homeostasis in C. auris.
“Comparative transcriptomic profiling and mechanistic studies indicated aprepitant/itraconazole interferes significantly with metal ion homeostasis and compromises the ROS detoxification ability of C. auris.”
The paper relies on this without support.
All genes that demonstrated differential expression in response to aprepitant/itraconazole treatments have orthologs in other Candida species.
“since all genes that demonstrated differential expression in response to aprepitant/itraconazole treatments have orthologs in other Candida species”
The paper relies on this without support.
Metal ion homeostasis is critical for multiple biological processes, including redox regulatory mechanisms.
“Since metal ion homeostasis is critical for multiple biological processes, including redox regulatory mechanisms”
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?
Candida auris infections frequently resist two classes of antifungal drugs, azoles and polyenes.
“C. auris infections frequently resist two classes of antifungal drugs, azoles and polyenes [8,9].”
From Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant <i>Candida auris</i> (2024) · cites this paper as [9]
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.
ROS fold increases conflict with the reported percentages
MajorA 300% increase over the untreated control corresponds to four times the control ROS level, not eight times. A 600% increase corresponds to seven times the control level, not approximately 15 times.
“aprepitant by itself compromised the ROS detoxification ability of C. auris, resulting in elevated ROS levels (eight-times higher compared to the untreated control). This effect was even more pronounced with the aprepitant/itraconazole combination which generated ~ 15-times more ROS levels, compared to the untreated control.”
“aprepitant (at 10 µg/ml) significantly increased the intracellular ROS levels by ~ 300% relative to the untreated control, while itraconazole treatment (at 1 µg/ml) significantly increased the ROS levels by 270% relative to the untreated control. On the other hand, the aprepitant/itraconazole combination resulted in a more prominent effect by increasing the ROS production by ~ 600% relative to the untreated control.”
Synergy is claimed for all C. auris isolates despite two additive results
MinorThe text calls the interaction synergistic against all tested C. auris isolates, but its Table 1 summary says two of the ten interactions were additive.
“The potent synergistic interaction observed between aprepitant and itraconazole against all C. auris isolates tested”
“resulting in a synergistic relationship observed against eight isolates (ƩFICI ranged from 0.14 to 0.31) and an additive relationship observed against two isolates (ƩFICI = 0.52).”
Time-kill assay duration is both 24 and 48 hours
MinorThe methods describe a 24-hour time-kill assay with a final measurement at 24 hours, whereas the Figure 1 caption says the agents were evaluated over 48 hours.
“Test agents were evaluated against C. auris AR0390 over a 48-hour incubation period at 35 °C.”
“Cells were incubated with aprepitant (10 µg/ml), itraconazole (1 µg/ml), or a combination of both agents for 24 h at 35°C. Following incubation, the number of viable cells was determined at specific time points (0, 6, 12, and 24 h).”
The screening isolate AR0390 is assigned two species
MinorThe initial-screen result calls AR0390 C. albicans, while the methods identify the screened AR0390 isolate as C. auris.
“Our initial screen identified aprepitant (an antiemetic agent) as a potent hit compound that restored the antifungal activity of fluconazole against the multidrug-resistant strain C. albicans AR0390.”
“The library was screened at 16 µM against C. auris AR0390 in the presence or absence of a subinhibitory concentration of fluconazole (32 µg/ml).”
Differential-expression significance cutoffs differ
MinorThe methods specify a corrected P-value cutoff of 0.005, but the transcriptomic results specify an adjusted P-value cutoff of 0.05 for identifying differentially expressed genes.
“A corrected P-value of 0.005 and an absolute foldchange of two was set as the threshold for significant differential expression.”
“Genes with an adjusted P-value <0.05 and that showed greater than a two-fold (up or down) change in expression were considered differentially expressed.”
Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482 · see citing works
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs
Altschul, S. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.17.3389 · Cited by 73,302 · see citing works
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364 · see citing works
clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters
Yu, G., Wang, L.-G., Han, Y., & He, Q.-Y. (2012) · OMICS: A Journal of Integrative Biology · doi:10.1089/omi.2011.0118 · Cited by 36,259 · see citing works
fastp: an ultra-fast all-in-one FASTQ preprocessor
(2018) · doi:10.1093/bioinformatics/bty560 · Cited by 29,721 · see citing works
featureCounts: an efficient general purpose program for assigning sequence reads to genomic features
Liao, Y., Smyth, G. K., & Shi, W. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btt656 · Cited by 27,219 · see citing works
HISAT: a fast spliced aligner with low memory requirements
Kim, D., Langmead, B., & Salzberg, S. L. (2015) · Nature Methods · doi:10.1038/nmeth.3317 · Cited by 24,112 · see citing works
A scaling normalization method for differential expression analysis of RNA-seq data
Robinson, M. D., & Oshlack, A. (2010) · Genome Biology · doi:10.1186/gb-2010-11-3-r25 · Cited by 7,876 · see citing works
Metal ions in biological catalysis: from enzyme databases to general principles
Andreini, C., Bertini, I., Cavallaro, G., Holliday, G. L., & Thornton, J. M. (2008) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-008-0404-5 · Cited by 1,150 · see citing works
Current and emerging azole antifungal agents
Sheehan, D. J., Hitchcock, C. A., & Sibley, C. M. (1999) · Clinical Microbiology Reviews · doi:10.1128/cmr.12.1.40 · Cited by 1,137 · see citing works
<i>Candida albicans</i> Biofilms and Human Disease
Nobile, C. J., & Johnson, A. D. (2015) · Annual Review of Microbiology · doi:10.1146/annurev-micro-091014-104330 · Cited by 1,057 · see citing works
<i>Candida</i> Infections of Medical Devices
Kojic, E. M., & Darouiche, R. O. (2004) · Clinical Microbiology Reviews · doi:10.1128/cmr.17.2.255-267.2004 · Cited by 1,055 · see citing works
Azole Antifungal Resistance in Candida albicans and Emerging Non-albicans Candida Species
Whaley, S. G., Berkow, E. L., Rybak, J. M., Nishimoto, A. T., Barker, K. S., & Rogers, P. D. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.02173 · Cited by 900 · see citing works
Chowdhary, A., Sharma, C., & Meis, J. F. (2017) · PLOS Pathogens · doi:10.1371/journal.ppat.1006290 · Cited by 750 · see citing works
Candida Biofilms: Threats, Challenges, and Promising Strategies
Cavalheiro, M., & Teixeira, M. C. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00028 · Cited by 690 · see citing works
Combination approaches to combat multidrug-resistant bacteria
Worthington, R. J., & Melander, C. (2013) · Trends in Biotechnology · doi:10.1016/j.tibtech.2012.12.006 · Cited by 625 · see citing works
Candida auris: a Review of the Literature
Jeffery-Smith, A., Taori, S. K., Schelenz, S., Jeffery, K. J., Johnson, E. M., Borman, A. M., Candida auris Incident Management Team, Manuel, R. J., & Brown, C. S. (2017) · Clinical Microbiology Reviews · doi:10.1128/cmr.00029-17 · Cited by 610 · see citing works
<i>Candida</i> biofilms on implanted biomaterials: a clinically significant problem
Ramage, G., MartÃnez, J. P., & López-Ribot, J. L. (2006) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2006.00117.x · Cited by 575 · see citing works
Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae
Jordá, T., & Puig, S. (2020) · Genes · doi:10.3390/genes11070795 · Cited by 489 · see citing works
Antifungal resistance: current trends and future strategies to combat
Wiederhold, N. P. (2017) · Infection and Drug Resistance · doi:10.2147/idr.s124918 · Cited by 477 · see citing works
<i>Candida auris</i> : The recent emergence of a multidrug-resistant fungal pathogen
Forsberg, K., Woodworth, K., Walters, M., Berkow, E. L., Jackson, B., Chiller, T., & Vallabhaneni, S. (2019) · Medical Mycology · doi:10.1093/mmy/myy054 · Cited by 421 · see citing works
Current Concepts in Antifungal Pharmacology
Lewis, R. E. (2011) · Mayo Clinic Proceedings · doi:10.4065/mcp.2011.0247 · Cited by 386 · see citing works
Nanoparticle-Mediated Combination Therapy: Two-in-One Approach for Cancer
Gurunathan, S., Kang, M.-H., Qasim, M., & Kim, J.-H. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103264 · Cited by 367 · see citing works
Azole antifungals: 35 years of invasive fungal infection management
Allen, D., Wilson, D., Drew, R., & Perfect, J. (2015) · Expert Review of Anti-infective Therapy · doi:10.1586/14787210.2015.1032939 · Cited by 255 · see citing works
Henry, K. W., Nickels, J. T., & Edlind, T. D. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.10.2693-2700.2000 · Cited by 216 · see citing works
Iron and Reactive Oxygen Species: Friends or Foes of Cancer Cells?
Bystrom, L. M., Guzman, M. L., & Rivella, S. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2012.5014 · Cited by 212 · see citing works
Reactive Oxygen Species-Inducing Antifungal Agents and Their Activity Against Fungal Biofilms
Delattin, N., Cammue, B. P., & Thevissen, K. (2014) · Future Medicinal Chemistry · doi:10.4155/fmc.13.189 · Cited by 189 · see citing works
Chau, A. S., Mendrick, C. A., Sabatelli, F. J., Loebenberg, D., & McNicholas, P. M. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.6.2124-2131.2004 · Cited by 187 · see citing works
Prasad, T., Chandra, A., Mukhopadhyay, C. K., & Prasad, R. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00653-06 · Cited by 149 · see citing works
Candida auris : An emerging multidrug-resistant pathogen
Sears, D., & Schwartz, B. S. (2017) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2017.08.017 · Cited by 146 · see citing works
Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent
Thangamani, S., Mohammad, H. T., Abushahba, M. F. N., Hamed, M. I., Sobreira, T. J. P., Hedrick, V., Paul, L. N., & Seleem, M. N. (2015) · Scientific Reports · doi:10.1038/srep16407 · Cited by 138 · see citing works
Self-citationFungal persister cells: The basis for recalcitrant infections?
Wuyts, J., Van Dijck, P., & Holtappels, M. (2018) · PLOS Pathogens · doi:10.1371/journal.ppat.1007301 · Cited by 136 · see citing works
Conserved Role for Biofilm Matrix Polysaccharides in <i>Candida auris</i> Drug Resistance
Dominguez, E. G., Zarnowski, R., Choy, H. L., Zhao, M., Sanchez, H., Nett, J. E., & Andes, D. R. (2019) · mSphere · doi:10.1128/mspheredirect.00680-18 · Cited by 132 · see citing works
Pizzorno, A., Padey, B., Terrier, O., & Rosa-Calatrava, M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00531 · Cited by 122 · see citing works
Lara, H. H., Ixtepan-Turrent, L., Jose Yacaman, M., & Lopez-Ribot, J. (2020) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.9b20708 · Cited by 116 · see citing works
Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles
Hu, C., Zhou, M., Wang, W., Sun, X., Yarden, O., & Li, S. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.00009 · Cited by 114 · see citing works
Thangamani, S., Eldesouky, H. E., Mohammad, H. T., Pascuzzi, P. E., Avramova, L. V., Hazbun, T. R., & Seleem, M. N. (2016) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2016.09.029 · Cited by 113 · see citing works
Self-citationFiori, A., & Van Dijck, P. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.06017-11 · Cited by 112 · see citing works
The role of metals in enzyme activity.
Riordan, J. F. (1977) · PubMed · Cited by 100 · see citing works
Chiang, C.-Y., Uzoma, I., Moore, R. T., Gilbert, M., Duplantier, A. J., & Panchal, R. G. (2018) · mBio · doi:10.1128/mbio.01932-17 · Cited by 95 · see citing works
Chang, W., Liu, J., Zhang, M., Shi, H., Zheng, S., Jin, X., Gao, Y., Wang, S., Ji, A., & Lou, H. (2018) · Nature Communications · doi:10.1038/s41467-018-07633-9 · Cited by 91 · see citing works
Thangamani, S., Maland, M., Mohammad, H., Pascuzzi, P. E., Avramova, L., Koehler, C. M., Hazbun, T. R., & Seleem, M. N. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00004 · Cited by 90 · see citing works
Self-citationEldesouky, H. E., Li, X., Abutaleb, N. S., Mohammad, H., & Seleem, M. N. (2018) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2018.08.016 · Cited by 90 · see citing works
Self-citationSCY-078 is fungicidal against Candida species in time-kill studies
Scorneaux, B., Angulo, D., Borroto-Esoda, K., Ghannoum, M., Peel, M., & Wring, S. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01961-16 · Cited by 88 · see citing works
Gu, W., Guo, D., Zhang, L., Xu, D., & Sun, S. (2016) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.03046-15 · Cited by 80 · see citing works
Hepatocellular Toxicity of Imidazole and Triazole Antimycotic Agents
Haegler, P., Joerin, L., Krähenbühl, S., & Bouitbir, J. (2017) · Toxicological Sciences · doi:10.1093/toxsci/kfx029 · Cited by 79 · see citing works
To what extent do structural changes in catalytic metal sites affect enzyme function?
Valasatava, Y., Rosato, A., Furnham, N., Thornton, J. M., & Andreini, C. (2018) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2017.11.002 · Cited by 77 · see citing works
Tewari, R. K., Hadacek, F., Sassmann, S., & Lang, I. (2013) · Environmental and Experimental Botany · doi:10.1016/j.envexpbot.2013.03.006 · Cited by 72 · see citing works
Hameed, S., Dhamgaye, S., Singh, A., Goswami, S. K., & Prasad, R. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018684 · Cited by 69 · see citing works
Chen, Y., Lehman, V. N., Averette, A. F., Perfect, J. R., & Heitman, J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057672 · Cited by 69 · see citing works
Candida auris: An emerging pathogen “incognito”?
Nett, J. E. (2019) · PLOS Pathogens · doi:10.1371/journal.ppat.1007638 · Cited by 69 · see citing works
Sun, L.-M., Liao, K., Liang, S., Yu, P.-H., & Wang, D.-Y. (2015) · Journal of Applied Microbiology · doi:10.1111/jam.12737 · Cited by 67 · see citing works
Optimizing antifungal choice and administration
Andes, D. (2013) · Current Medical Research and Opinion · doi:10.1185/03007995.2012.761135 · Cited by 63 · see citing works
Key issues concerning fungistatic versus fungicidal drugs
Graybill, J. R., Burgess, D. S., & Hardin, T. C. (1997) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/bf01575120 · Cited by 59 · see citing works
Reversal of Azole Resistance in Candida albicans by Sulfa Antibacterial Drugs
Eldesouky, H. E., Mayhoub, A., Hazbun, T. R., & Seleem, M. N. (2018) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00701-17 · Cited by 55 · see citing works
Self-citationEldesouky, H. E., Salama, E. A., Li, X., Hazbun, T. R., Mayhoub, A. S., & Seleem, M. N. (2020) · Scientific Reports · doi:10.1038/s41598-020-64571-7 · Cited by 55 · see citing works
Self-citationMohammad, H. T., Eldesouky, H. E., Hazbun, T. R., Mayhoub, A. S., & Seleem, M. N. (2019) · Scientific Reports · doi:10.1038/s41598-019-55379-1 · Cited by 54 · see citing works
Self-citationMilbemycins: More than Efflux Inhibitors for Fungal Pathogens
Silva, L. V., Sanguinetti, M., Vandeputte, P., Torelli, R., Rochat, B., & Sanglard, D. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02040-12 · Cited by 49 · see citing works
Kobayashi, T., Kakeya, H., Miyazaki, T., Izumikawa, K., Yanagihara, K., Ohno, H., Yamamoto, Y., Tashiro, T., & Kohno, S. (2011) · Japanese Journal of Infectious Diseases · doi:10.7883/yoken.64.292 · Cited by 48 · cited 1× · see citing works
“Notably, iron homeostasis has been regarded as a potential target for other azole chemosensitizing agents such as doxycycline and lactoferrin [65,66].”
BackgroundTamura, M., Cueno, M. E., Abe, K., Kamio, N., Ochiai, K., & Imai, K. (2018) · Cell Stress and Chaperones · doi:10.1007/s12192-018-0922-1 · Cited by 37 · see citing works
Derivates of the Antifungal Peptide Cm-p5 Inhibit Development of Candida auris Biofilms In Vitro
Kubiczek, D. H., Raber, H. F., González-García, M., Morales-Vicente, F., Ständker, L., Otero‐González, A. J., & Rosenau, F. (2020) · Antibiotics · doi:10.3390/antibiotics9070363 · Cited by 36 · see citing works
De Cremer, K., De Brucker, K., Staes, I., Peeters, A., Van den Driessche, F., Coenye, T., Cammue, B. P. A., & Thevissen, K. (2016) · Scientific Reports · doi:10.1038/srep27463 · Cited by 34 · see citing works
Eldesouky, H. E., Salama, E. A., Hazbun, T. R., Mayhoub, A. S., & Seleem, M. N. (2020) · Scientific Reports · doi:10.1038/s41598-020-62976-y · Cited by 33 · see citing works
Self-citationMohammad, H., Elghazawy, N. H., Eldesouky, H. E., Hegazy, Y. A., Younis, W., Avrimova, L., Hazbun, T., Arafa, R. K., & Seleem, M. N. (2018) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.7b00215 · Cited by 29 · see citing works
Self-citationThe Ins and Outs of Azole Antifungal Drug Resistance: Molecular Mechanisms of Transport
Zavřel, M., Esquivel, B. D., & White, T. C. (2017) · Springer eBooks · doi:10.1007/978-1-4939-0694-9_29 · Cited by 20 · see citing works
Investigation of aryl isonitrile compounds with potent, broad-spectrum antifungal activity
Mohammad, H. T., Kyei‐Baffour, K., Younis, W., Davis, D. C., Eldesouky, H. E., Seleem, M. N., & Dai, M. (2017) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.03.035 · Cited by 8 · see citing works
Self-citationThe Ins and Outs of Azole Antifungal Drug Resistance: Molecular Mechanisms of Transport
Zavřel, M., Esquivel, B. D., & White, T. C. (2014) · Springer eBooks · doi:10.1007/978-1-4939-0667-3_29-1 · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 4
- Whaley SG, 2016, Front Microbiol, 7, 2173
- Kubiczek D, 2020, Antibiotics (Basel), 9
- 10.2307/2346101 · DOI
- Riordan JF, 1977, Ann Clin Lab Sci, 7, 119
Cited by
Sorted by citations
Salama, E. A., Elgammal, Y., Wijeratne, A., Lanman, N. A., Utturkar, S. M., Farhangian, A., Li, J., Meunier, B., Hazbun, T. R., & Seleem, M. N. (2024) · Emerging Microbes & Infections · doi:10.1080/22221751.2024.2322649 · Cited by 16 · see citing works
Self-citation
- Authors
- Eldesouky, H. E., Lanman, N. A., Hazbun, T. R., & Seleem, M. N.
- Affiliations
- Purdue University West Lafayette (US)
- Corresponding author
- Seleem, Mohamed N.
- Venue
- Virulence
- Publisher
- Informa UK Limited
- Published
- 2020-10-26
- Volume
- 11
- Issue
- 1
- Pages
- 1466-1481
- ISSN
- 2150-5594 (ISSN-L)
- 2150-5608
- PMC
- PMC7588212
- OpenAlex
- W3093911145
- Semantic Scholar
- c1eb85883ce08e0bc51a30e76c68cf4ee7847101
- Cited by
- 37
- References
- 67
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 11 · 2023: 8 · 2022: 5 · 2021: 7
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Virulence (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- VTechWorks (Virginia Tech) (submittedVersion, cc-by)
- Purdue e-Pubs (Purdue University System) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Purdue University
- Centers for Disease Control and Prevention
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- aprepitant, Candida auris, azole resistance, itraconazole, drug synergy, metal homeostasis, biofilm formation, combination antifungal therapy, chemosensitizers, reactive oxygen species scavenging, Caenorhabditis elegans infection model, Candida albicans, Candida tropicalis, Candida parapsilosis, Candida krusei, gene expression profiling
- MeSH terms
- Aprepitant, Animals, Antiemetics, Antifungal Agents, Azoles, Candida, Candidiasis, Drug Synergism, Homeostasis, Ions, Metals, Microbial Sensitivity Tests, Caenorhabditis elegans, Biofilms, Gene Expression Profiling, Drug Resistance, Multiple, Fungal
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
