Cross‐species discovery of syncretic drug combinations that potentiate the antifungal fluconazole
Open accessAbstract
Resistance to widely used fungistatic drugs, particularly to the ergosterol biosynthesis inhibitor fluconazole, threatens millions of immunocompromised patients susceptible to invasive fungal infections. The dense network structure of synthetic lethal genetic interactions in yeast suggests that combinatorial network inhibition may afford increased drug efficacy and specificity. We carried out systematic screens with a bioactive library enriched for off-patent drugs to identify compounds that potentiate fluconazole action in pathogenic Candida and Cryptococcus strains and the model yeast Saccharomyces. Many compounds exhibited species- or genus-specific synergism, and often improved fluconazole from fungistatic to fungicidal activity. Mode of action studies revealed two classes of synergistic compound, which either perturbed membrane permeability or inhibited sphingolipid biosynthesis. Synergistic drug interactions were rationalized by global genetic interaction networks and, notably, higher order drug combinations further potentiated the activity of fluconazole. Synergistic combinations were active against fluconazole-resistant clinical isolates and an in vivo model of Cryptococcus infection. The systematic repurposing of approved drugs against a spectrum of pathogens thus identifies network vulnerabilities that may be exploited to increase the activity and repertoire of antifungal agents.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Phenotypic screening in combination with older, now less effective antimicrobials might uncover therapeutic value in vast regions of chemical space that have previously been ignored.
“Phenotypic screening in combination with older, now less effective antimicrobials might uncover therapeutic value in vast regions of chemical space that have previously been ignored (Ejim et al., 2011; Spitzer et al., 2011).”
From A Fungal-Selective Cytochrome bc1 Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance (2016) · cites this paper as Spitzer et al., 2011
Previously, the drug repositioning approach has successfully identified FLC adjuvants.
“Previously, the drug repositioning approach has successfully identified FLC adjuvants [17,18,19,20,21].”
From Pitavastatin Calcium Confers Fungicidal Properties to Fluconazole by Inhibiting Ubiquinone Biosynthesis and Generating Reactive Oxygen Species (2024) · cites this paper as [19]
The primary screen identified several drugs with known fluconazole chemosensitizing activities, including simvastatin, atorvastatin, lovastatin, artemisinin, amiodarone, sulfamethoxazole, doxycycline, nisoldipine, and tamoxifen.
“In addition and as expected, the primary screen identified several drugs with known fluconazole chemosensitizing activities, such as the cholesterol-lowering agents; simvastatin, atorvastatin, and lovastatin, artemisinin, amiodarone, sulfamethoxazole, doxycycline, and the calcineurin inhibitors nisoldipine and tamoxifen19–25.”
From Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species (2020) · cites this paper as [20]
Subsequent studies to identify compounds that augment amphotericin B and fluconazole activity against Cryptococcus spp. identified numerous antipsychotic drugs, including sertraline, trifluoperazine and thioridazine.
“Subsequent studies to identify compounds that augment amphotericin B and fluconazole activity against Cryptococcus spp. also identified numerous antipsychotic drugs, including sertraline, trifluoperazine and thioridazine112,113.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [112]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 68 · Cited by 183
Research works printed but not linked: 1
- Richardson M, Warnock D (2003) Fungal Infection: Diagnosis and Management. Oxford: Blackwell Publishing
- Authors
- Spitzer, M., Griffiths, E., Blakely, K. M., Wildenhain, J., Ejim, L., Rossi, L., De Pascale, G., Curak, J., Brown, E., Tyers, M., & Wright, G. D.
- Affiliations
- Wellcome Centre for Cell Biology (GB)
- University of British Columbia (CA)
- Michael G. DeGroote Institute for Infectious Disease Research (CA)
- Corresponding author
- Tyers, Mike
- Wright, Gerard D
- ORCID
- Venue
- Molecular Systems Biology
- Published
- 2011-06-21
- Volume
- 7
- Issue
- 1
- Pages
- 499-499
- ISSN
- 1744-4292 (ISSN-L)
- PMC
- PMC3159983
- OpenAlex
- W2116536284
- Cited by
- 183
- References
- 68
- Citations by year
- 2026: 9 · 2025: 2 · 2024: 10 · 2023: 6 · 2022: 9 · 2021: 7 · 2020: 19 · 2019: 13 · 2018: 12 · 2017: 13 · 2016: 17 · 2015: 14 · 2014: 10 · 2013: 17 · 2012: 18
- FWCI
- 10.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Systems Biology (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- European Commission (223411)
- Canadian Institutes of Health Research (FRN79488)
- 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
- antifungal synergy, drug repurposing, Candida, Cryptococcus, Saccharomyces cerevisiae, synthetic genetic interactions, membrane permeability, fungicidal activity, antifungal resistance, invasive fungal infections, immunocompromised patients
- MeSH terms
- Animals, Antifungal Agents, Candida, Cryptococcus, Drug Synergism, Ergosterol, Insecta, Microbial Sensitivity Tests, Saccharomyces, Species Specificity, Fluconazole, Computational Biology, Gene Expression Profiling, Drug Resistance, 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.
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
