Known Antimicrobials Versus Nortriptyline in Candida albicans: Repositioning an Old Drug for New Targets
Open accessAbstract
Candida albicans has the capacity to develop resistance to commonly used antimicrobials, and to solve this problem, drug repositioning and new drug combinations are being studied. Nortriptyline, a tricyclic antidepressant, was shown to have the capacity to inhibit biofilm and hyphae formation, along with the ability to efficiently kill cells in a mature biofilm. To use nortriptyline as a new antimicrobial, or in combination with known drugs to increase their actions, it is important to characterize in more detail the effects of this drug on the target species. In this study, the Candida albicans GRACE™ collection and a Haplo insufficiency profiling were employed to identify the potential targets of nortriptyline, and to classify, in a parallel screening with amphotericin B, caspofungin, and fluconazole, general multi-drug resistance genes. The results identified mutants that, during biofilm formation and upon treatment of a mature biofilm, are sensitive or tolerant to nortriptyline, or to general drug treatments. Gene ontology analysis recognized the categories of ribosome biogenesis and spliceosome as enriched upon treatment with the tricyclic antidepressant, while mutants in oxidative stress response and general stress response were commonly retrieved upon treatment with any other drug. The data presented suggest that nortriptyline can be considered a “new” antimicrobial drug with large potential for application to in vivo infection models.
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Written from the paper’s full text.
TL;DR
Using the *Candida albicans* GRACE™ collection and haploinsufficiency profiling, this study compared nortriptyline with amphotericin B, caspofungin, and fluconazole to identify drug-specific and general multidrug-resistance genes. Nortriptyline showed distinct targets and detox responses, supporting its repositioning as an antimicrobial candidate for in vivo testing.
Key findings
- In triplicate screening of 2372 GRACE™ strains, 15 mutants were sensitive to nortriptyline only during early biofilm formation, 38 were sensitive in mature biofilm, 44 were tolerant during biofilm formation, and 34 were tolerant in mature biofilm.
- General drug phenotypes included 26 strains sensitive to all treatments during biofilm formation, 25 sensitive to nortriptyline, amphotericin B, and caspofungin, and five sensitive to all four drugs; 12 mutants were tolerant overall (3 during biofilm formation, 9 in mature biofilm), with six tolerant to all four drugs.
- Nortriptyline enriched ribosome biogenesis, spliceosome, RNA metabolism, oxidative phosphorylation, and fatty acid biosynthesis categories depending on condition, while known antimicrobials commonly retrieved oxidative stress and general stress response categories.
- Oxidative/nitrosative assays showed oxidized glutathione with caspofungin and fluconazole, increased nitric oxide in all conditions, and increased ROS and propidium iodide–positive dead cells with nortriptyline and caspofungin; Ames testing found 600 µM nortriptyline increased base-shift revertants but low frameshifts, with no real mutagenic effect at experimental concentrations and reduced mutation frequency with S9.
Methods
- Chemogenomic haploinsufficiency profiling used the *C. albicans* GRACE™ collection (2372 strains, CaSS1 background) without tetracycline except for selected mutants, screened in parallel with nortriptyline, amphotericin B, caspofungin, and fluconazole at condition A/B concentrations (nortriptyline 10/20 µM, amphotericin B 0.5/1 µM, caspofungin 15/20 µM, fluconazole 200/400 µM).
- Biofilm assays grew mutants for 90 min, then exposed them to drugs during biofilm formation for 48 h or treated mature biofilms for 48 h; growth was measured spectrophotometrically or by XTT reduction.
- Additional assays included glutathione and nitric oxide measurements, ROS/propidium iodide flow cytometry, qRT-PCR of transporter genes, Ames testing with *S. typhimurium* TA98 and TA100, and GO/KEGG plus STRING network analysis.
Limitations
- Stated in the paper: many *C. albicans* genes remain uncharacterized, with functions often putative, predicted, or inferred from *S. cerevisiae*; the role of nitric oxide in yeast and *C. albicans* physiology and nitrosative stress targets still needs clarification; DNA damage was observed only at higher nortriptyline concentrations than those used experimentally.
- Evident from the text: all experiments are in vitro using one *C. albicans* mutant collection/background and biofilm models, with no in vivo infection model, so clinical potential remains untested.
- Evident from the text: effects may be concentration- and condition-specific, as screening used selected subinhibitory concentrations and two biofilm stages, and fluconazole had a small impact under the test conditions.
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- Findingown data
The enriched GO categories for nortriptyline-tolerant mutants during biofilm formation were spliceosome system, mismatch repair/DNA replication, and histidine metabolism.
“The spliceosome system, mismatch repair/DNA replication, and histidine metabolism were the enriched GO categories (Figure 2c).”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
The addition of S9 liver fraction reduced the mutation rate frequency to that of the control.
“The addition of S9 liver fraction reduced the mutation rate frequency to that of the control.”
Quote in the paperNot a substantial claim - Findingown data
The highest concentrations of nortriptyline tested (600 μM) induced a low increase in frameshifts.
“The Ames test with S. typhimurium TA98 and TA100 was performed and the data in Supplementary Table S6 showed that the highest concentrations of NOR tested (600 µM) induced an increase in base shift revertants, but a low increase in frameshifts.”
Quote in the paperNot a substantial claim - Findingown data
Network analysis of the 38 mature-biofilm nortriptyline-sensitive mutants revealed enrichment in genes related to spliceosome activity, ribosome machinery, and fatty acid biosynthesis.
“Network analysis for these revealed an enrichment in genes related to spliceosome activity, ribosome machinery, and fatty acid biosynthesis (Figure 2b).”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
Beside NOR, CAS was the most effective drug in the conditions tested.
“Beside NOR, the most effective drug in the conditions tested was CAS”
Quote in the paperNot a substantial claim
- Findingown data
The Ames test with S. typhimurium TA98 and TA100 showed that the highest concentrations of nortriptyline tested (600 μM) induced an increase in base shift revertants.
“The Ames test with S. typhimurium TA98 and TA100 was performed and the data in Supplementary Table S6 showed that the highest concentrations of NOR tested (600 µM) induced an increase in base shift revertants, but a low increase in frameshifts.”
Quote in the paperSubstantial claim - Findingown data
Exposure to nortriptyline and caspofungin increased the ROS content per cell.
“Exposure to NOR and CAS increased the ROS content per cell, as well as the percentage of dead cells (Figure 3c–e).”
Quote in the paperSubstantial claim - Findingown data
Basal expression of the selected transporter genes was absent in a mature biofilm grown for 48 h.
“Basal expression of the selected genes was absent in a mature biofilm grown for 48 h (Figure 4).”
Quote in the paperNot a substantial claim - Findingown data
According to KEGG, the more representative categories for mature-biofilm nortriptyline-tolerant mutants were ribosome biogenesis and cell cycle/meiosis control.
“According to KEGG, the more representative categories in this condition were again ribosome biogenesis and cell cycle/meiosis control.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
Mutants in oxidative stress response and general stress response were commonly retrieved upon treatment with any other drug.
“Gene ontology analysis recognized the categories of ribosome biogenesis and spliceosome as enriched upon treatment with the tricyclic antidepressant, while mutants in oxidative stress response and general stress response were commonly retrieved upon treatment with any other drug.”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
The number of dead cells increased in the presented experiments (PI+ cells).
“indeed, the number of dead cells also increased in the presented experiments (see PI+ cells).”
Quote in the paperSubstantial claim - Findingown data
A triplicate screening of the GRACETM library compiled a list of strains sensitive to nortriptyline.
“With a triplicate screening of the library, a list of strains sensitive to NOR was compiled (Figure 1a, Supplementary Table S2).”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
Four strains demonstrated sensitivity to all treatments both at the beginning of colonization and in a mature biofilm.
“As displayed in Supplementary Table S5, 26 strains were sensitive to all the treatments during biofilm formation, while four demonstrated the same phenotype at the beginning of the colonization as well as in a mature biofilm.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
The sensitive and tolerant mutants belong to the GO categories ribosome biogenesis, RNA splicing, and mRNA processing.
“They belong to the GO categories: ribosome biogenesis, RNA splicing, and mRNA processing”
Quote in the paperSubstantial claim - Findingown data
An increase in nitric oxide was observed in all conditions tested.
“The oxidized glutathione was present when cells were treated with CAS and FLU, while an increase in NO was observed in all conditions (Figure 3b).”
Quote in the paperNot a substantial claim - Findingown data
For nortriptyline-sensitive mutants, GO Process Slim Mapper enriched categories were RNA metabolism, transport, organelle organization, ribosome biogenesis, cellular protein modification, and response to chemicals.
“For the sensitive mutants, the enriched categories identified with Gene Ontology (GO) Process Slim Mapper (Supplementary Table S3 were RNA metabolism, transport, organelle organization, ribosome biogenesis, cellular protein modification, and response to chemicals.”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
NAG3, NAG4, and 19.5720 are strongly induced by nortriptyline after 24 h.
“NAG3, NAG4, and 19.5720 are strongly induced by NOR, while CDR2 and 19.304 are upregulated in the presence of AMB and CAS.”
Quote in the paperSubstantial claim - Findingown data
Inactivating the second copy of selected genes (pmu5Δ/pmu5Δ, dal9Δ/dal9Δ, pet127Δ/pet127Δ) with tetracycline makes those mutants more tolerant to nortriptyline even in a mature biofilm.
“Inactivating the second copy of the gene as well (pmu5Δ/pmu5Δ, dal9Δ/dal9Δ, pet127Δ/pet127Δ) by adding tetracycline to the growth medium makes the selected mutants more tolerant to the TCA even in a mature biofilm condition (Supplementary Figure S1).”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
The enriched GO Process Slim Mapper categories for mature-biofilm nortriptyline-tolerant mutants were organelle organization, transport, RNA metabolic process, cellular protein modification, response to chemical or stress, and cell cycle.
“The enriched categories identified with GO Process Slim Mapper (Supplementary Table S3) were organelle organization, transport, RNA metabolic process, cellular protein modification, response to chemical or stress, and cell cycle.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
During biofilm formation, only three mutants were tolerant to the antimicrobials used.
“During the formation of a biofilm, only three mutants were tolerant to the antimicrobials used, while nine were tolerant even when a mature biofilm was challenged (Table S5).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
ROS synthesis is increased upon treatment with NOR.
“The synthesis of ROS was increased upon treatment with NOR.”
Quote in the paperSubstantial claim - Findingown data
Network analysis of the third-category knock-out genes and their first interactors showed enrichment of KEGG pathways ribosome biogenesis and oxidative phosphorylation.
“Considering the networks generated by these knock-out genes, and their first interactors, an enrichment of the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway’s (medium confidence and False Discovery Rate FDR ˂ 0.005) ribosome biogenesis and oxidative phosphorylation was observed (Figure 2a).”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
Thirty mutants were sensitive to all tested drugs except FLU during biofilm formation or maintenance.
“Thirty mutants were sensitive to all the tested drugs (except for FLU, which had a small impact in the test conditions) during biofilm formation or during its maintenance”
Quote in the paperSubstantial claim - Findingown data
NOR induces NO production.
“In our case, the presence of NOR also induces NO production.”
Quote in the paperNot a substantial claim - Findingown data
The better characterized deleted genes among general sensitive mutants are involved in oxidative stress responses (GND1, MPS1), regulation of filamentous growth and stress responses (VPS4, VPS23, CDC9, ENP1), control of transcription and translation (TFB1, MED8, SSU72, NEP1, PAB1), and transport (LYP1, orf19.304, NAG4).
“The better characterized deleted genes are involved in oxidative stress responses (GND1, MPS1), regulation of filamentous growth and stress responses (VPS4, VPS23, CDC9, ENP1), control of transcription and translation (TFB1, MED8, SSU72, NEP1, PAB1), and transport (LYP1, orf19.304, NAG4).”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingcitation
A different concentration of proteins involved in mismatch repair and DNA replication makes the yeast more tolerant to NOR.
“A different concentration of proteins involved in mismatch repair and DNA replication makes the yeast more tolerant to NOR”
Quote in the paperSubstantial claim - Findingown data
There were more changes in gene expression after 24 h than after 4 h.
“There were more changes after 24 h (Figure 4b and Supplementary Figure S2).”
Quote in the paperNot a substantial claim - Findingown data
Gene ontology analysis identified ribosome biogenesis and spliceosome as enriched categories upon treatment with nortriptyline.
“Gene ontology analysis recognized the categories of ribosome biogenesis and spliceosome as enriched upon treatment with the tricyclic antidepressant, while mutants in oxidative stress response and general stress response were commonly retrieved upon treatment with any other drug.”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
Six strains displayed tolerance to all four drugs, with deleted genes PGA12, CPR52, RTS2, PAA11, orf19.305, and orf19.1180.
“These 12 mutated genetic functions are poorly characterized, and the ones with a known activity correspond to PLB1, a phospholipase B involved in virulence, and SHA3 and SCH9, involved in stress responses and in filamentous growth; among these, mutants’ tolerance to all four drugs was displayed by six strains (Figure 1d), where the deleted genes were PGA12, CPR52, RTS2, PAA11, orf19.305, and orf19”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
25 mutants were sensitive to nortriptyline, amphotericin B, and caspofungin.
“Overall, 25 mutants were sensitive to NOR, AMB, and CAS, while five were sensitive to all four drugs tested (Figure 1c).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
Nine mutants were tolerant to the antimicrobials used even when a mature biofilm was challenged.
“During the formation of a biofilm, only three mutants were tolerant to the antimicrobials used, while nine were tolerant even when a mature biofilm was challenged (Table S5).”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
MDR1 is upregulated when amphotericin B, caspofungin, and fluconazole are present after 24 h.
“The expression of CDR1 is induced by AMB and FLU; the expression of CDR2 increased when AMB or CAS is present in the medium; and MDR1 is upregulated when AMB, CAS, and FLU are present.”
Quote in the paperNot a substantial claim - Findingown data
26 strains were sensitive to all treatments during biofilm formation.
“As displayed in Supplementary Table S5, 26 strains were sensitive to all the treatments during biofilm formation, while four demonstrated the same phenotype at the beginning of the colonization as well as in a mature biofilm.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
Mutants in oxidative phosphorylation and fatty acid metabolism are more sensitive to treatment with NOR.
“Mutants in oxidative phosphorylation and fatty acid metabolism are more sensitive to the treatment with NOR.”
Quote in the paperSubstantial claim - Findingown data
In the HIP screening, transporter genes whose deletion increased sensitivity specifically only to nortriptyline were FLU1, NAG3, and 19.5720.
“In the HIP screening, transporter genes whose deletion increased sensitivity to all drugs tested (19.304, NAG4, 19.3444) or specifically only to NOR (FLU1, NAG3, 19.5720) were identified.”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
Five mutants were sensitive to all four drugs tested (nortriptyline, amphotericin B, caspofungin, and fluconazole).
“Overall, 25 mutants were sensitive to NOR, AMB, and CAS, while five were sensitive to all four drugs tested (Figure 1c).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
CDR2 is induced by nortriptyline and amphotericin B after 4 h.
“FLU1 is repressed in the presence of NOR, CAS, and FLU; CDR1 is induced by NOR; CDR2 is induced by NOR and AMB; and 19.304 by CAS.”
Quote in the paperNot a substantial claim - Findingown data
The expression of CDR1 is induced by amphotericin B and fluconazole after 24 h.
“The expression of CDR1 is induced by AMB and FLU; the expression of CDR2 increased when AMB or CAS is present in the medium; and MDR1 is upregulated when AMB, CAS, and FLU are present.”
Quote in the paperNot a substantial claim - Findingown data
Twelve mutants were more tolerant than the control.
“while 12 mutants were more tolerant than the control.”
Quote in the paperSubstantial claim - Findingown data
FLU1 is repressed in the presence of nortriptyline, caspofungin, and fluconazole after 4 h.
“FLU1 is repressed in the presence of NOR, CAS, and FLU; CDR1 is induced by NOR; CDR2 is induced by NOR and AMB; and 19.304 by CAS.”
Quote in the paperNot a substantial claim - Findingown data
Incubation with any of the drugs for 4 h induced the expression of only a few genes, but not in all of the conditions tested.
“Incubation with any of the drugs for 4 h induced the expression of only a few genes, but not in all of the conditions tested (Figure 4a and Supplementary Figure S2).”
Quote in the paperNot a substantial claim - Findingown data
Repressing the second copy of selected genes (cdc19Δ/cdc19Δ, mlh3Δ/mlh3Δ, spt8Δ/spt8Δ) with tetracycline made those mutants sensitive to nortriptyline even in a mature biofilm.
“When the expression of the second copy of the gene was also repressed in selected mutants (cdc19Δ/cdc19Δ, mlh3Δ/mlh3Δ, spt8Δ/spt8Δ) by adding tetracycline, the identified mutants became sensitive to NOR even in a mature biofilm (Supplementary Figure S1).”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
Exposure to nortriptyline and caspofungin increased the percentage of dead cells.
“Exposure to NOR and CAS increased the ROS content per cell, as well as the percentage of dead cells (Figure 3c–e).”
Quote in the paperSubstantial claim - Findingown data
Oxidized glutathione was present when cells were treated with caspofungin and fluconazole.
“The oxidized glutathione was present when cells were treated with CAS and FLU, while an increase in NO was observed in all conditions (Figure 3b).”
Quote in the paperNot a substantial claim - Findingown data
19.304 is induced by caspofungin, fluconazole, and nortriptyline after 24 h.
“FLU1 is repressed by CAS, FLU, and NOR, while 19.304 is induced by the same antimicrobials.”
Quote in the paperNot a substantial claim - Findingown data
In the HIP screening, transporter genes whose deletion increased sensitivity to all drugs tested were 19.304, NAG4, and 19.3444.
“In the HIP screening, transporter genes whose deletion increased sensitivity to all drugs tested (19.304, NAG4, 19.3444) or specifically only to NOR (FLU1, NAG3, 19.5720) were identified.”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
At concentrations closer to those used in the experiments described above, a real mutagenic effect of nortriptyline was not evident.
“At concentrations closer to those used in the experiments described above, a real mutagenic effect was not evident.”
Quote in the paperNot a substantial claim - Findingown data
34 additional mutants could grow better than the reference strain even when a mature biofilm was challenged with nortriptyline.
“Moreover, 34 additional mutants could grow better than the reference strain even when a mature biofilm was challenged (Figure 2d).”
Quote in the paperNot a substantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingown data
The screening of the C. albicans GRACETM library identified mutants with different growth phenotypes when grown in the presence of nortriptyline.
“The screening of the GRACE™ library allowed to identify mutants with a different GP when grown in the presence of NOR.”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
- Findingreasoning
A decreased level of the least characterized Flu1, Nag3, and product of orf19.5720 transporters makes C. albicans more sensitive to NOR.
“but a decreased level of the least characterized Flu1, Nag3, and product of orf19.5720 transporters makes C. albicans more sensitive to NOR.”
Quote in the paperSubstantial claim - Findingown data
Expression of MDR1, CDR1, and CDR2 is unaffected by the presence of NOR.
“whereas the expressions of MDR1, CDR1, and CDR2 were unaffected by the presence of NOR.”
Quote in the paperSubstantial claim - Findingown data
A lower concentration of the proteins encoded by MDR1, CDR1, and CDR2 does not affect sensitivity to NOR.
“A lower concentration of the proteins encoded by these genes does not affect the sensitivity to NOR”
Quote in the paperSubstantial claim - Findingnone given
Lower levels of orf19.304 product, a putative fungal-specific MDR protein, and Nag4 make the yeast more sensitive to NOR, AMB, and CAS.
“Lower levels of orf19.304 product, a putative fungal specific MDR protein, and Nag4 make the yeast more sensitive to NOR, AMB, and CAS.”
Quote in the paperSubstantial claim - Findingown data
Expression of orf19.5720, NAG3, and NAG4 increases especially in the presence of NOR.
“Expression of orf19.5720, NAG3, and NAG4 increases especially in the presence of NOR”
Quote in the paperSubstantial claim - Interpretationown data
The retrieved data suggest that mitochondria are among the targets of NOR.
“The retrieved data seem to suggest that mitochondria are among the targets of NOR, a characteristic common to other central nervous system drugs [33].”
Quote in the paperSubstantial claim - Premisecitation
Nortriptyline induces lysis of C. albicans cells.
“NOR induces lysis of cells [11]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Caldara, 2018, Tricyclic antidepressants inhibit Candida albicans growth and biofilm formation, Int. J. Antimicrob. Agents source
Not checked in the free run.
- Interpretationreasoning
The targeting of ribosome biogenesis and RNA-related functions by NOR suggests mis-regulation of protein synthesis.
“This result suggests a miss-regulation of protein synthesis.”
Quote in the paperSubstantial claim - Interpretationcitation
Ribosome biogenesis, RNA splicing, and mRNA processing are general targets of antimicrobial drugs.
“indicating that these functions are general targets of antimicrobials drugs [42].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Vediyappan, 2010, Interaction of Candida albicans biofilms with antifungals: Transcriptional response and binding of antifungals to beta-glucans, Antimicrob. Agents Chemother. source
Not checked in the free run.
- Premisecitation
Candida albicans has the capacity to develop resistance to commonly used antimicrobials.
“Candida albicans has the capacity to develop resistance to commonly used antimicrobials”
- Also stated in: § 1. Introduction · plain
“with the capacity to develop resistance to commonly used antifungals.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Wisplinghoff, 2014, Nosocomial bloodstream infections due to Candida spp. in the USA: Species distribution, clinical features and antifungal susceptibilities, Int. J. Antimicrob. Agents source
Not checked in the free run.
- Also stated in: § 1. Introduction · plain
- Interpretationown data
Nortriptyline can be considered a new antimicrobial drug with large potential for application to in vivo infection models.
“The data presented suggest that nortriptyline can be considered a “new” antimicrobial drug with large potential for application to in vivo infection models.”
Quote in the paperSubstantial claim- Rests on an assumption: In vitro activity and target identification of nortriptyline against C. albicans biofilms predict its potential efficacy in in vivo infection models.
- Premisecitation
Exposure of a mature biofilm to AMB or CAS changes the expression of ribosome biogenesis-related genes.
“Similarly, exposure of a mature biofilm to AMB or CAS changes the expression of ribosome biogenesis-related genes [42].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Vediyappan, 2010, Interaction of Candida albicans biofilms with antifungals: Transcriptional response and binding of antifungals to beta-glucans, Antimicrob. Agents Chemother. source
Not checked in the free run.
- Premisecitation
NOR has antimicrobial activity against Candida albicans.
“Another antidepressant with antimicrobial properties that was shown to be active against Candida albicans is NOR [11]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Caldara, 2018, Tricyclic antidepressants inhibit Candida albicans growth and biofilm formation, Int. J. Antimicrob. Agents source
Not checked in the free run.
- Interpretationcitation
The listed genes might be identified as C. albicans-specific MDR genes, as very little overlap is displayed between these elements and the MDR genes described in S. cerevisiae.
“The genes listed (in Supplementary Data) might be identified as C. albicans specific MDR genes [46], as very little overlap is displayed between these elements and the MDR genes described in S. cerevisiae [46,47].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [46] Arendrup, 2017, Multidrug-resistant candida: Epidemiology, molecular mechanisms, and treatment, J. Infect. Dis. source
Not checked in the free run.
- cites [47] Lacka, 2008, Multidrug resistance in fungi, Postepy Biochem.
Not checked in the free run.
- Premisecitation
The cell lysis induced by nortriptyline, local anesthetics, and antipsychotic phenothiazine is related to their amphiphilic structures and surfactant activity, which disturb cell membrane functionality.
“This phenomenon is related to their amphiphilic structures and their surfactant activity, which are able to disturb cell membrane functionality [11,13].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [11] Caldara, 2018, Tricyclic antidepressants inhibit Candida albicans growth and biofilm formation, Int. J. Antimicrob. Agents source
Not checked in the free run.
- cites [13] Uesono, 2008, Local Anesthetics, Antipsychotic Phenothiazines, and Cationic Surfactants Shut Down Intracellular Reactions through Membrane Perturbation in Yeast, Biosci. Biotechnol. Biochem. source
Not checked in the free run.
- Interpretationreasoning
The product of orf19.5720, Nag3, and Nag4 may also be relevant for acquired antimicrobial resistance.
“In addition, this suggests that product of orf19.5720, Nag3, and Nag4 may also be relevant for acquired antimicrobial resistance.”
Quote in the paperSubstantial claim - Premisecitation
The antimicrobial activity of NOR is synergic with other commercial drugs.
“the antimicrobial activity of NOR is synergic with other commercial drugs [11]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Caldara, 2018, Tricyclic antidepressants inhibit Candida albicans growth and biofilm formation, Int. J. Antimicrob. Agents source
Not checked in the free run.
- Interpretationnone given
NOR elicits different detox strategies.
“NOR elicits different detox strategies.”
Quote in the paperNot a substantial claim - Premisecitation
The combination of deletion in the three common ABC transporters does not eliminate drug resistance.
“This hypothesis is supported by the observation that the combination of deletion in the three common ABC transporters does not eliminate drug resistance [29]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Mukherjee, 2003, Mechanism of fluconazole resistance in Candida albicans biofilms: Phase-specific role of efflux pumps and membrane sterols, Infect. Immun. source
Not checked in the free run.
- Interpretationown data
NOR has different targets than those of known antimicrobials.
“this TCA has different targets than those of known antimicrobials”
Quote in the paperSubstantial claim - Interpretationcitation
Other mechanisms could be involved in drug resistance.
“and suggests that other mechanisms could be involved.”
Quote in the paperSubstantial claim
- May combine two claims. 13
- The quote only partly states this claim. 8
- Classified as probably not a substantial claim. 7
May combine two claims.
Findingnone givenTargets of NOR include ribosome biogenesis and machinery, RNA binding, and the RNA splicing apparatus.
“Targets of NOR are also ribosome biogenesis and machinery, RNA binding, and the RNA splicing apparatus.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataCDR2 and 19.304 are upregulated in the presence of amphotericin B and caspofungin after 24 h.
“NAG3, NAG4, and 19.5720 are strongly induced by NOR, while CDR2 and 19.304 are upregulated in the presence of AMB and CAS.”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown data19.304 is induced by caspofungin after 4 h.
“FLU1 is repressed in the presence of NOR, CAS, and FLU; CDR1 is induced by NOR; CDR2 is induced by NOR and AMB; and 19.304 by CAS.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingnone givenThe third category of nortriptyline-sensitive mutants includes 15 mutants, most of which are poorly characterized.
“The third category includes 15 mutants, most of which are poorly characterized.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationMany of the targets are regulated by the transcription factor Hap43.
“It is interesting to note that many of the targets are regulated by the transcription factor Hap43, a protein with pleiotropic functions (i.e., iron homeostasis, chromosome biogenesis, and filamentation [44]).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe growth phenotypes of the mutants separate them into three categories: sensitive to nortriptyline and other known antimicrobials in all conditions; sensitive when nortriptyline was added during the first stages of biofilm formation and to the mature biofilm; and sensitive to nortriptyline only during the first stages of biofilm formation.
“The displayed GPs allow the separation of the mutants into three categories: the first one corresponds to mutants sensitive to NOR, as well as to other known antimicrobials and in all the growing conditions tested; the second one corresponds to mutants sensitive when NOR was added during the first stages of biofilm formation and to the mature biofilm; and the third corresponds to strains sensitive”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
The quote only partly states this claim.
Findingown dataCDR1 is induced by nortriptyline after 4 h.
“FLU1 is repressed in the presence of NOR, CAS, and FLU; CDR1 is induced by NOR; CDR2 is induced by NOR and AMB; and 19.304 by CAS.”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataA total of 38 mutants were identified as sensitive to nortriptyline within a mature biofilm.
“A total of 38 mutants were identified as sensitive to the TCA also within a mature biofilm.”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
The quote only partly states this claim.
Findingown data44 strains grew better than the wild type when challenged with nortriptyline during biofilm formation.
“As shown in Supplementary Table S4 and Figure 1b, 44 strains grew better than the WT when challenged with the TCA during biofilm formation.”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
The quote only partly states this claim.
Findingown dataThe expression of CDR2 increased when amphotericin B or caspofungin is present in the medium after 24 h.
“The expression of CDR1 is induced by AMB and FLU; the expression of CDR2 increased when AMB or CAS is present in the medium; and MDR1 is upregulated when AMB, CAS, and FLU are present.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe 12 mutated genetic functions in tolerant mutants are poorly characterized, and the ones with known activity correspond to PLB1, SHA3, and SCH9.
“These 12 mutated genetic functions are poorly characterized, and the ones with a known activity correspond to PLB1, a phospholipase B involved in virulence, and SHA3 and SCH9, involved in stress responses and in filamentous growth; among these, mutants’ tolerance to all four drugs was displayed by six strains (Figure 1d), where the deleted genes were PGA12, CPR52, RTS2, PAA11, orf19.305, and orf19”
Quote in the paperNot a substantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
May combine two claims.
FindingcitationIn CAS treatment, glutathione oxidation state was lower, while ROS, NO, and PI+ cells were higher.
“where the glutathione oxidation state was lower, while ROS, NO, and PI+ cells were higher”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationThe NOR tolerance phenotype is not linked to DNA damage, as DNA damage was observed only at drug concentrations higher than those used in this work and higher than those used to treat depression syndromes.
“a phenotype not linked to DNA damage, as the latter was observed only at drug concentrations higher than those used in this work, and to that employed to treat depression syndromes [43].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [43] Caldara, 2017, Off-target effects of neuroleptics and antidepressants on Saccharomyces cerevisiae, Toxicol. Sci.
Not checked in the free run.
The quote only partly states this claim.
Findingown dataFLU1 is repressed by caspofungin, fluconazole, and nortriptyline after 24 h.
“FLU1 is repressed by CAS, FLU, and NOR, while 19.304 is induced by the same antimicrobials.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingnone givenAmong the general sensitive mutants, most deleted ORFs are poorly characterized and their role is often only predicted.
“Among those, most of the deleted open reading frames (ORFs) have been poorly characterized and the role attributed is often only predicted.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
May combine two claims.
Findingown dataIn a mature biofilm, expression of these transporters is almost absent and changes only slightly after 4 h of treatment with antimicrobials.
“Overall, the expression of these transporters in a mature biofilm is almost absent and changes only slightly after 4 h of treatment with antimicrobials”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter 24 h, all these genes are upregulated, but their expression is different between treatments.
“instead, after 24 h, all genes are upregulated, but their expression is different between treatments.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationNortriptyline inhibits biofilm and hyphae formation and efficiently kills cells in a mature C. albicans biofilm.
“Nortriptyline, a tricyclic antidepressant, was shown to have the capacity to inhibit biofilm and hyphae formation, along with the ability to efficiently kill cells in a mature biofilm.”
- Also stated in: § 1. Introduction · plain
“Nortriptyline (NOR), the most used tricyclic antidepressants (TCA) up until the introduction of selective serotonin re-uptake inhibitors, or SSRIs, was shown to have the capacity to inhibit biofilm and hyphae formation and to efficiently kill cells in a mature biofilm of C. albicans [11].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Caldara, 2018, Tricyclic antidepressants inhibit Candida albicans growth and biofilm formation, Int. J. Antimicrob. Agents source
Not checked in the free run.
- Also stated in: § 1. Introduction · plain
The quote only partly states this claim.
InterpretationcitationThe effect of increased ROS and dead cells may have clinical relevance because oxidative stress reduces microbial pathogenicity by enhanced killing by macrophages.
“Overall, this is an effect that may have clinical relevance because it is known that oxidative stress reduces microbial pathogenicity by enhanced killing by macrophages [35], as shown for A. fumigatus [36].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [35] Traven, 2011, Mitochondria and Fungal Pathogenesis: Drug Tolerance, Virulence, and Potential for Antifungal Therapy, Eukaryot. Cell source
Not checked in the free run.
- cites [36] Magnani, 2008, Silencing of mitochondrial alternative oxidase gene of Aspergillus fumigatus enhances reactive oxygen species production and killing of the fungus by macrophages, J. Bioenerg. Biomembr. source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationOxidative stress induces cell damage and cell death.
“Oxidative stress has been suggested to induce cell damage and cell death [34]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34] Peralta, 2017, Usnic Acid Activity on Oxidative and Nitrosative Stress of Azole-Resistant Candida albicans Biofilm, Planta Med.
Not checked in the free run.
May combine two claims.
PremisecitationCAS induces ROS and cell death.
“confirming previous data showing the capacity of CAS to induce ROS and cell death [37].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Chi, 2014, Deletion of AIF1 but not of YCA1/MCA1 protects Saccharomyces cerevisiae and Candida albicans cells from caspofungin-induced programmed cell death, Microb. Cell
Not checked in the free run.
May combine two claims.
InterpretationreasoningData suggest that mutants in mismatch and DNA repair better tolerate treatment with nortriptyline, suggesting that treatment with nortriptyline is related to DNA damage.
“Data reported in the previous paragraphs suggest that mutants in mismatch and DNA repair better tolerate a treatment with NOR, suggesting that treatment with the TCA is related to DNA damage.”
Quote in the paperSubstantial claim- The authors state this as an assumption: A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn higher organisms, NO is involved in cell signaling and maintenance of homeostasis, but high levels of this metabolite lead to chemical stress.
“In higher organisms, NO is involved in cell signaling and maintenance of homeostasis, but high levels of this metabolite lead to chemical stress, possibly also contributing to the induction and progression of diseases [38,39].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [38] Datta, 2014, Correlation of oxidant status with oxidative tissue damage in patients with rheumatoid arthritis, Clin. Rheumatol. source
Not checked in the free run.
- cites [39] Cheng, 2017, Inducible Nitric Oxide Synthase in the Carcinogenesis of Gastrointestinal Cancers, Antioxid. Redox Signal. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationExpression of the ATP binding cassette transporters MDR1, CDR1, and CDR2 is often higher in resistant clinical isolates.
“Indeed, expression of these ATP binding cassette transporters (ABC) is often higher in resistant clinical isolates [46,48].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [46] Arendrup, 2017, Multidrug-resistant candida: Epidemiology, molecular mechanisms, and treatment, J. Infect. Dis. source
Not checked in the free run.
- cites [48] Barker, 2006, Recent insights into the mechanisms of antifungal resistance, Curr. Infect. Dis. Rep. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningIn this study, gene function is often reported as putative, predicted, or inferred based on known orthologues from Saccharomyces cerevisiae.
“Several Candida albicans genes still need to be characterized, and this is also reflected in this study as gene function is often reported as putative, predicted, or inferred (based on known orthologues from Saccharomyces cerevisiae).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe detox-response in Candida albicans to this TCA is specific and different from the response to other antifungals.
“This shows how the detox-response in Candida albicans to this TCA is specific and different from the response to other antifungals.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationreasoningNOR could be repositioned as a new antimicrobial drug ready to be tested on in vivo models to investigate its potential clinical application.
“These data suggest NOR could be repositioned as a “new” antimicrobial drug ready to be tested on in vivo models to investigate its potential clinical application.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
A heterozygous deletion strain is particularly sensitive to a drug when the product of the deleted gene is the target of the drug being tested.
“This procedure is based on the assumption that a heterozygous deletion strain would be particularly sensitive to the presence of a drug whenever the product of the deleted gene is the target of the molecule being tested.”
The paper relies on this without support.
In vitro activity and target identification of nortriptyline against C. albicans biofilms predict its potential efficacy in in vivo infection models.
“The data presented suggest that nortriptyline can be considered a “new” antimicrobial drug with large potential for application to in vivo infection models.”
The paper relies on this without support.
Little is known about NOR's potential target(s) and molecular effects in Candida albicans.
“but little is known about its potential target(s) and molecular effects.”
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?
Chemogenomic profiling with a haploinsufficiency approach focused on C. albicans mutants identified oxidative phosphorylation, fatty acid metabolism, ribosome biogenesis and machinery, RNA binding, and RNA splicing apparatus as possible targets of nortriptyline.
“Chemogenomic profiling with a haploinsufficiency approach focused on C. albicans mutants identified the following processes and systems as possible targets of nortriptyline: oxidative phosphorylation, fatty acid metabolism, ribosome biogenesis and machinery, RNA binding, and the RNA splicing apparatus [73,106].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [73]
Treatment of a C. albicans mutants library with nortriptyline identified mutants specifically sensitive or tolerant to this drug and others sharing phenotype when treated with common antifungals.
“Indeed, treatment of a C. albicans mutants library with nortriptyline identified mutants that are specifically sensitive or tolerant to this drug and others that share the same phenotype when treated with common antifungals [73].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [73]
TCAs are active against Candida spp., where they inhibit hyphal formation, lyse cells, and kill them even in a mature biofilm.
“Works based on TCAs showed that this class of molecules was active against Candida spp., where they inhibited hyphal formation, lysed the cells, and killed them even in a mature biofilm [72,73].”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [73]
Mitochondria are one of the targets of nortriptyline.
“The work suggests that mitochondria are one of the targets of nortriptyline (Figure 1), although it is not clear which function, carried out by this organelle (i.e., ATP production and oxidative phosphorylation, maintenance of the redox state, cell survival or apoptosis induction, lipid peroxidation), is affected.”
From Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications (2021) · cites this paper as [73]
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.
Sensitive and tolerant criteria overlap
MinorA mutant growing at least three times as much as the WT meets the stated criterion for tolerance, but it also meets the stated criterion for sensitivity: growth of at least one-third of the WT. The criteria therefore cannot distinguish the two reported groups.
“A mutant was considered sensitive when its growth was at least one-third of that displayed by the WT”
“tolerant when the GP was at least three times that of the WT.”
FLU1 repression conflicts with claim that all genes were upregulated
MinorThe discussion states that all examined transporter genes were upregulated after 24 hours, whereas the results report that FLU1 was repressed by three of the drugs at that time.
“after 24 h, all genes are upregulated”
“FLU1 is repressed by CAS, FLU, and NOR”
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Applications of Cold Atmospheric Pressure Plasma in Dentistry
Borges, A. C., Kostov, K. G., Pessoa, R. S., de Abreu, G. M. A., Lima, G. D. M. G., Figueira, L. W., & Koga‐Ito, C. Y. (2021) · Applied Sciences · doi:10.3390/app11051975 · Cited by 82 · see citing works
<i>Candida albicans</i>targets that potentially synergize with fluconazole
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Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications
Caldara, M., & Marmiroli, N. (2021) · Pharmaceuticals · doi:10.3390/ph14090915 · Cited by 54 · see citing works
Self-citationTargeting Virulence Factors of Candida albicans with Natural Products
Bu, Q., Bao, M.-Y., Yang, Y., Wang, T.-M., & Wang, C. (2022) · Foods · doi:10.3390/foods11192951 · Cited by 46 · see citing works
Candida Albicans Virulence Factors and Its Pathogenicity
Henriques, M., & Silva, S. (2021) · Microorganisms · doi:10.3390/microorganisms9040704 · Cited by 39 · see citing works
In vivo evaluation of the antifungal activity of sertraline against Aspergillus fumigatus
Treviño‐Rangel, R. D. J., Villanueva‐Lozano, H., Méndez-Galomo, K. S., Solís-Villegas, E. M., Becerril-García, M. A., Montoya, A. M., Robledo-Leal, E., & González, G. M. (2018) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dky455 · Cited by 28 · see citing works
Mechanisms of Azole Potentiation: Insights from Drug Repurposing Approaches
Xiong, J., Lu, H., & Jiang, Y. (2025) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.4c00657 · Cited by 20 · see citing works
Cabral, V. P. D. F., Rodrigues, D. S., Sá, L. G. D. A. V., Moreira, L. E. A., da Silva, C. R., Neto, J. B. D. A., da Costa, É. R. M., Ferreira, T. L., de Oliveira, L. C., de Souza, B. O., et al. (2024) · Brazilian Journal of Microbiology · doi:10.1007/s42770-024-01459-y · Cited by 5 · see citing works
- Authors
- Caldara, M., & Marmiroli, N.
- Affiliations
- University of Parma (IT)
- Corresponding author
- Caldara, Marina
- Venue
- Microorganisms
- Publisher
- MDPI AG
- Published
- 2020-05-15
- Volume
- 8
- Issue
- 5
- Pages
- 742
- ISSN
- 2076-2607 (ISSN-L)
- PMC
- PMC7284794
- OpenAlex
- W3024401325
- Semantic Scholar
- 12e5e5181cc210c5a12c9d838658989a3e8dc25a
- Cited by
- 8
- References
- 48
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2021: 4 · 2018: 1
- FWCI
- 0.16
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Microorganisms (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Università degli Studi di Parma (CALD.INCENTIFIL17)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- nortriptyline, Candida albicans, drug repurposing, antifungal resistance, biofilm formation, ribosome biogenesis, spliceosome, oxidative stress response, stress response, amphotericin B, caspofungin, fluconazole, tricyclic antidepressants
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