Effect of Nitric Oxide on the Antifungal Activity of Oxidative Stress and Azoles Against Candida albicans
Open accessAbstract
Nitric oxide (NO) is a small molecule with a wide range of biological activities in mammalian and bacteria. However, the role of NO in fungi, especially Candida albicans, is not clear. In this study, we confirmed the generation of endogenous NO in C. albicans, and found that the production of endogenous NO in C. albicans was associated with nitric oxide synthase pathway. Our results further indicated that the production of endogenous NO in C. albicans was reduced under oxidative stress such as menadione or H2O2 treatment. Meanwhile, exogenous NO donor, sodium nitroprusside (SNP), synergized with H2O2 against C. albicans. Interestingly, SNP could inhibit the antifungal effect of azoles against C. albicans in vitro, suggesting that NO might be involved in the resistance of C. albicans to antifungals. Collectively, this study demonstrated the production of endogenous NO in C. albicans, and indicated that NO may play an important role in the response of C. albicans to oxidative stress and azoles.
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Written from the paper’s full text.
TL;DR
This study reports that *Candida albicans* produces endogenous nitric oxide (NO) via a nitric oxide synthase-like route, and that this production drops under oxidative stress. Exogenous NO synergizes with H₂O₂ to kill the fungus but protects it from azole antifungals in vitro.
Key findings
- *C. albicans* SC5314 showed intracellular NO fluorescence with DAF-FM DA; treatment with 100 mM L-NAME reduced NO production by 65% (P < 0.001), suggesting a NOS-like pathway.
- Endogenous NO was significantly inhibited by menadione and H₂O₂ (P < 0.001).
- SNP alone at 3.7–7.5 µg/ml had no significant antifungal effect, but 3.7 µg/ml SNP combined with 2 mM H₂O₂ completely killed *C. albicans*.
- SNP attenuated the antifungal activity of 1 µg/ml fluconazole and 0.15 µg/ml miconazole against strains SC5314 and Y0109, with a stronger effect at higher SNP concentrations.
Methods
- Two *C. albicans* strains, SC5314 and Y0109, were grown in YPD at 30 °C; NO was detected with DAF-FM DA using confocal microscopy and flow cytometry, with L-NAME as a NOS inhibitor.
- Time-kill assays used 5 × 10⁴ cells/ml, various antifungal agents or SNP/H₂O₂, incubation at 30 °C with shaking, and OD₆₀₀ readings at 0, 12, 16, 20, and 24 h.
- Data came from three independent experiments; comparisons used Student’s t test and are reported as means ± SD.
Limitations
- The paper does not state limitations explicitly.
- Evident from the text: all experiments were in vitro and used only two *C. albicans* strains, so host interactions and strain diversity are not addressed.
- Evident from the text: the NOS-like mechanism is inferred from inhibitor and fluorescence data; the authors note that bioinformatic analysis did not identify classical NOS homologs (data not shown), and the azole-protective result conflicts with an earlier study using a different NO donor and temperature.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
8 of 17 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured
- Premisecitation
C. albicans employs strategies to evade oxidative killing by innate immune cells.
“Nevertheless, C. albicans employed strategies to evade the oxidative killing by innate immune cells [4].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [4] Dantas Ada S, Day A, Ikeh M, Kos I, Achan B, Quinn J (2015) Oxidative stress responses in the human fungal pathogen, Candida albicans. Biomolecules 5:142–165. doi: 10.3390/biom5010142 source
- Findingown data
SNP at concentrations from 3.7 to 7.5 lg/ml does not show significant antifungal effect against C. albicans.
“Although 2 mM H 2 O 2 could inhibit the growth of C. albicans to some degree, SNP ranging from 3.7 to 7.5 lg/ml didn't show significant antifungal effect (Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
Candida albicans produces endogenous nitric oxide (NO).
“In this study, we confirmed the generation of endogenous NO in C. albicans”
- Also stated in: § NO Production in C. albicans · hedged
“After incubation with DAF-FM DA, C. albicans showed bright fluorescence under confocal microscope, indicating NO production (Fig. 1a).”
- Also stated in: § Discussion · boosted
“Collectively, we demonstrated the existence of endogenous NO in C. albicans, and showed that the production of NO in C. albicans involves a NOS-like pathway.”
Quote in the paperSubstantial claim - Also stated in: § NO Production in C. albicans · hedged
- Findingown data
The attenuation of azole antifungal effect by SNP becomes more obvious as SNP concentration increases.
“Moreover, with the concentration of SNP increasing, the effect was more obvious (Fig. 4a, c).”
Quote in the paperSubstantial claim - Findingown data
Bioinformatic analysis of the C. albicans genome failed to identify sequences homologous to known NOS.
“We have carried out bioinformatic analysis on the C. albicans genome but failed to identify sequences that are homologous to known NOS (data not shown).”
Quote in the paperSubstantial claim
- Findingown data
Exogenous NO (SNP) attenuates the antifungal effect of azoles (FCZ and MCZ) against C. albicans in vitro.
“Unexpectedly, exogenous NO could attenuate the antifungal effect of azoles.”
- Also stated in: § NO Protects C. albicans Against Azoles · plain
“However, the addition of 3.7 lg/ml SNP attenuated the antifungal effect of azoles.”
- Also stated in: § NO Protects C. albicans Against Azoles · plain
“To confirm this finding, another clinical C. albicans strain Y0109 was used, and the results were consistent with the finding on C. albicans SC5314 (Fig. 4b, d).”
Quote in the paperSubstantial claim - Also stated in: § NO Protects C. albicans Against Azoles · plain
- Findingown data
The combination of 3.7 lg/ml SNP and 2 mM H2O2 kills C. albicans completely.
“Interestingly, the combination of 3.7 lg/ml SNP and 2 mM H 2 O 2 killed C. albicans completely (Fig. 3b).”
Quote in the paperSubstantial claim - Interpretationown data
Exogenous NO (SNP) synergizes with H2O2 against C. albicans.
“Meanwhile, exogenous NO donor, sodium nitroprusside (SNP), synergized with H 2 O 2 against C. albicans.”
- Also stated in: § NO is Involved in the Response of C. albicans to Oxidative Stress · plain
“Collectively, our results showed that the generation of endogenous NO in C. albicans could be inhibited by oxidative stress and exogenous NO could synergize with H 2 O 2 against C. albicans.”
- Also stated in: § Discussion · boosted
“More specifically, exogenous NO has significant synergistic effect with H 2 O 2 against C. albicans.”
Quote in the paperSubstantial claim - Also stated in: § NO is Involved in the Response of C. albicans to Oxidative Stress · plain
- Interpretationown data
NO is involved in the response of C. albicans to oxidative stress.
“indicated that NO may play an important role in the response of C. albicans to oxidative stress and azoles.”
- Also stated in: § Discussion · boosted
“We demonstrate that NO is involved in the response of C. albicans to oxidative stress.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Interpretationown data
The reduction of endogenous NO production in C. albicans under oxidative stress may be a feedback protection mechanism of C. albicans to respond to oxidative stress.
“Besides, our results indicated that the production of endogenous NO was reduced in C. albicans upon oxidative stress, which may be a feedback protection mechanism of C. albicans to response to oxidative stress.”
Quote in the paperSubstantial claim - Interpretationown data
NO may be involved in the resistance of C. albicans to antifungals.
“suggesting that NO might be involved in the resistance of C. albicans to antifungals.”
- Also stated in: § Discussion · hedged
“It is interesting to find that NO could protect C. albicans against azoles.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Interpretationown data
The production of endogenous NO in C. albicans is associated with a NOS-like pathway.
“found that the production of endogenous NO in C. albicans was associated with nitric oxide synthase pathway.”
- Also stated in: § NO Production in C. albicans · hedged
“Collectively, these findings suggested that NO could be produced by C. albicans, and the NO production was associated with a NOSlike biological effect.”
- Also stated in: § Discussion · boosted
“Collectively, we demonstrated the existence of endogenous NO in C. albicans, and showed that the production of NO in C. albicans involves a NOS-like pathway.”
Quote in the paperSubstantial claim - Also stated in: § NO Production in C. albicans · hedged
- Classified as probably not a substantial claim. 9
- The quote only partly states this claim. 3
- May combine two claims. 2
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNO plays an important role in the process of microorganism killing through oxidative stress in macrophage.
“Some previous studies reported that NO played an important role in the process of microorganism killing through oxidative stress in macrophage, which is consistent with our findings [26,27].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [26] Collette JR, Zhou H, Lorenz MC (2014) Candida albicans suppresses nitric oxide generation from macrophages via a secreted molecule. PLoS One 9:e96203. doi: 10.1371/journal.pone.0096203 source
The Introduction describes nitric-oxide-related reactive nitrogen species as macrophage antimicrobial effectors and reports reduced Candida-killing activity when iNOS was inhibited. It does not establish that NO kills microorganisms specifically through oxidative stress; it also says NO’s exact role in antifungal defense remains unresolved. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [27] Heilman BJ, Tadle AC, Pimentel LR, Mascharak PK (2013) Selective damage to hyphal form through light-induced delivery of nitric oxide to Candida albicans colonies. J Inorg Biochem 123:18–22. doi: 10.1016/j.jinorgbio.2013.02.003 source
Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
InterpretationreasoningThe different results between this study and McElhaney-Feser et al. [30] may be due to different experimental design (DETA-NO vs SNP and 37 °C vs 30 °C incubation).
“A previous finding indicated that NO was synergistic with azoles against C. albicans [30], but they did microdilution assays using DETA-NO (Diethylenetriamine NONOate) as the NO donor and 37 °C as the incubation temperature.The different results may be due to the different experimental design.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [30] McElhaney-Feser GE, Raulli RE, Cihlar RL (1998) Synergy of nitric oxide and azoles against Candida species in vitro. Antimicrob Agents Chemother 42:2342–2346 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn bacteria, NO generated by NOS increases resistance to a broad spectrum of antibiotics.
“Gusarov et al. [15] and Shatalin et al. [20] reported that in bacteria, NO generated by NOS increases the resistance of bacteria to a broad spectrum of antibiotics.”
- Also stated in: § Introduction · hedged
“It was reported that bacterial NOS are present in many grampositive species, which could increase the resistance of bacteria to a broad spectrum of antibiotics, enable the bacteria to survive and share habitats with antibiotic-producing microorganisms [15,20].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [15] Gusarov I, Shatalin K, Starodubtseva M, Nudler E (2009) Endogenous nitric oxide protects bacteria against a wide spectrum of antibiotics. Science 325:1380–1384. doi: 10.1126/science.1175439 source
- cites [20] Shatalin K, Gusarov I, Avetissova E, Shatalina Y, McQuade LE, Lippard SJ, Nudler E (2008) Bacillus anthracis-derived nitric oxide is essential for pathogen virulence and survival in macrophages. Proc Natl Acad Sci USA 105:1009–1013. doi: 10.1073/pnas.0710950105 source
- Also stated in: § Introduction · hedged
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThere have been a number of publications reporting the existence of NOS-like effect in bacteria, yeast, and plants.
“Nevertheless, there have been a number of publications reporting the existence of NOS-like effect in bacteria [15,16], yeast [17,18], and plants [19].”
Quote in the paperNot a substantial claim3 of 5 sources checked- cites [15] Gusarov I, Shatalin K, Starodubtseva M, Nudler E (2009) Endogenous nitric oxide protects bacteria against a wide spectrum of antibiotics. Science 325:1380–1384. doi: 10.1126/science.1175439 source
- cites [16] Popova TG, Teunis A, Vaseghi H, Zhou W, Espina V, Liotta LA, Popov SG (2015) Nitric oxide as a regulator of B. anthracis pathogenicity. Front Microbiol 6:921. doi: 10.3389/fmicb.2015.00921 source
- cites [17] Osorio NS, Carvalho A, Almeida AJ, Padilla-Lopez S, Leao C, Laranjinha J, Ludovico P, Pearce DA, Rodrigues F (2007) Nitric oxide signaling is disrupted in the yeast model for Batten disease. Mol Biol Cell 18:2755–2767. doi: 10.1091/mbc.E06-11-1053 source
- cites [18] Astuti RI, Watanabe D, Takagi H (2016) Nitric oxide signaling and its role in oxidative stress response in Schizosaccharomyces pombe. Nitric Oxide 52:29–40. doi: 10.1016/j.niox.2015.11.001 source
- cites [19] Besson-Bard A, Courtois C, Gauthier A, Dahan J, Dobrowolska G, Jeandroz S, Pugin A, Wendehenne D (2008) Nitric oxide in plants: production and cross-talk with Ca2+ signaling. Mol Plant 1:218–228. doi: 10.1093/mp/ssm016 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLow levels of NO exhibit a cytoprotective effect during stress from heat-shock or high hydrostatic pressure in S. cerevisiae.
“Moreover, Domitrovic et al. [23] reported that low levels of NO exhibited a cytoprotective effect during stress from heat-shock or high hydrostatic pressure in S. cerevisiae.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [23] Domitrovic T, Palhano FL, Barja-Fidalgo C, DeFreitas M, Orlando MT, Fernandes PM (2003) Role of nitric oxide in the response of Saccharomyces cerevisiae cells to heat shock and high hydrostatic pressure. FEMS Yeast Res 3:341–346 source
The quote only partly states this claim.
Findingown dataTreatment with the NOS inhibitor L-NAME (100 mM) reduces endogenous NO production in C. albicans by 65% (P < 0.001).
“Notably, after treatment with 100 mM NOS inhibitor L-NAME, no observable fluorescence was found (Fig. 1a).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataEndogenous NO production in C. albicans is significantly inhibited by menadione and H2O2 (P < 0.001).
“Our results further indicated that the production of endogenous NO in C. albicans was reduced under oxidative stress such as menadione or H 2 O 2 treatment.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFCZ (1 lg/ml) or MCZ (0.15 lg/ml) significantly inhibits the growth of C. albicans SC5314.
“As shown in Fig. 4a and c, 1 lg/ml FCZ or 0.15 lg/ml MCZ could inhibit the growth of C. albicans SC5314 significantly.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDAF-FM DA has been successfully used to detect NO production in yeast.
“A NO-selective probe DAF-FM DA, which has been successfully used to detect NO production in yeast was used in this study [18].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Astuti RI, Watanabe D, Takagi H (2016) Nitric oxide signaling and its role in oxidative stress response in Schizosaccharomyces pombe. Nitric Oxide 52:29–40. doi: 10.1016/j.niox.2015.11.001 source
May combine two claims.
PremisecitationNitric oxide dioxygenase coding gene in C. albicans is upregulated under oxidative stress or in macrophage, which could promote metabolism of NO to reduce oxidative stress.
“Consistently, it was reported that nitric oxide dioxygenase coding gene in C. albicans was upregulated under oxidative stress or in macrophage, by which C. albicans could promote the metabolism of NO to reduce oxidative stress [28,29].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [28] Arana DM, Nombela C, Pla J (2010) Fluconazole at subinhibitory concentrations induces the oxidative- and nitrosative-responsive genes TRR1, GRE2 and YHB1, and enhances the resistance of Candida albicans to phagocytes. J Antimicrob Chemother 65:54–62. doi: 10.1093/jac/dkp407 source
- cites [29] Lorenz MC, Bender JA, Fink GR (2004) Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell 3:1076–1087. doi: 10.1128/EC.3.5.1076-1087.2004 source
Classified as probably not a substantial claim.
PremisecitationL-NAME is a specific NOS inhibitor.
“After addition of a specific NOS inhibitor L-NAME (100 mM), cell suspensions were incubated at 30 °C under constant shaking (200 rpm) for 1 h [21].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Kig C, Temizkan G (2009) Nitric oxide as a signaling molecule in the fission yeast Schizosaccharomyces pombe. Protoplasma 238:59–66. doi: 10.1007/s00709-009-0074-3 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThree independent experiments were performed.
“Three independent experiments were performed.”
- Also stated in: § Discussion · plain
“The data are shown as means ± SDs from three independent experiments.”
Quote in the paperNot a substantial claim- Also stated in: § Discussion · plain
Classified as probably not a substantial claim.
PremisecitationSNP is a specific NO donor.
“SNP, a specific NO donor [21] was used in this work.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Kig C, Temizkan G (2009) Nitric oxide as a signaling molecule in the fission yeast Schizosaccharomyces pombe. Protoplasma 238:59–66. doi: 10.1007/s00709-009-0074-3 source
The paper relies on this without support.
The role and production of endogenous NO in C. albicans are not well established, and NO production in C. albicans has not previously been reported.
“However, the role of NO in fungi, especially Candida albicans, is not clear.”
“However, whether there is endogenous NO in C. albicans is unclear, and few study has focused on the role of NO in C. albicans up to now.”
“To date, NO production has not been reported in C. albicans.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
Cites a retracted work: 10.1016/s1567-1356(03)00039-4
InfoThe cited work was retracted on 2022-03-20 (notice 10.1093/femsyr/foac011), not before this paper was published (2016-04-09).
Cited work 10.1016/s1567-1356(03)00039-4 · retracted 2022-03-20 · notice 10.1093/femsyr/foac011 · this paper published 2016-04-09
“Domitrovic T, Palhano FL, Barja-Fidalgo C, DeFreitas M, Orlando MT, Fernandes PM (2003) Role of nitric oxide in the response of Saccharomyces cerevisiae cells to heat shock and high hydrostatic pressure. FEMS Yeast Res 3:341–346”
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Synergic activity of oligostyrylbenzenes with amphotericin B against Candida tropicalis biofilms
Quinteros, M. A., Tolosa, J., García-Martínez, J. C., Páez, P. L., & Paraje, M. G. (2021) · Yeast · doi:10.1002/yea.3672 · Cited by 7 · see citing works
Leveraging Vulnerabilities in Copper Trafficking for Synergistic Antifungal Activity
Denning-Jannace, C. A., James, K. J., Ortiz, C. M., Sturrock, G. R., Robison, A. T. R., Vaccaro, F. A., Kuhn, S. A., Fitzgerald, M. C., & Franz, K. J. (2025) · ACS Chemical Biology · doi:10.1021/acschembio.5c00525
- Authors
- Li, D.-D., Yang, C.-C., Liu, P., Wang, Y., & Sun, Y.
- Affiliations
- Chinese People's Armed Police General Hospital (CN)
- Chinese PLA General Hospital (CN)
- Second Military Medical University (CN)
- Corresponding author
- Wang, Yan
- Sun, Yan
- Venue
- Indian Journal of Microbiology
- Published
- 2016-04-09
- Volume
- 56
- Issue
- 2
- Pages
- 214-218
- ISSN
- 0046-8991 (ISSN-L)
- 0973-7715
- PMC
- PMC4984430
- OpenAlex
- W2318300255
- Cited by
- 8
- References
- 32
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2017: 1
- FWCI
- 0.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Indian Journal of Microbiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81573724, 81501730)
- Shanghai Pujiang Program (14PJD001)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- nitric oxide, Candida albicans, oxidative stress, azoles, antifungal resistance, nitric oxide synthase, sodium nitroprusside, hydrogen peroxide, menadione, endogenous nitric oxide production
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