Inhibition of Candida albicans by Fluvastatin Is Dependent on pH
Open accessAbstract
The cholesterol-lowering drug fluvastatin (FS) has an inhibitory effect on the growth of the pathogenic yeast Candida albicans that is dependent on the pH of the medium. At the low pH value of the vagina, FS is growth inhibitory at low and at high concentrations, while at intermediate concentrations (1–10 mM), it has no inhibitory effect. Examination of the effect of the common antifungal drug fluconazole in combination with FS demonstrates drug interactions in the low concentration range. Determination of intracellular stress and the activity of the FS target enzyme HMG-CoA reductase confirm our hypothesis that in the intermediate dose range adjustments to the sterol biosynthesis pathway can compensate for the action of FS. We conclude that the pH dependent uptake of FS across yeast membranes might make FS combination therapy an attractive possibility for treatment of vaginal C. albicans infections.
AI snapshot
Written from the paper’s full text.
TL;DR
Fluvastatin inhibits *Candida albicans* growth in a pH-dependent, nonlinear manner, with low and high concentrations active at acidic pH but intermediate concentrations ineffective. The findings suggest a possible low-dose fluvastatin/azole strategy for vaginal *C. albicans* infections, though synergy criteria were not met and the mechanism remains incompletely explained.
Key findings
- At pH 4.5, fluvastatin inhibited growth at low (0.5–1.0 μM) and high (>10 μM) concentrations but not at intermediate concentrations (1–10 μM); at pH 7.0 it showed a simple dose-response. Among six statins tested, fluvastatin was the only one with a nonlinear dose response.
- Addition of fluvastatin lowered the fluconazole MIC by at least a factor of four in all eight clinical isolates tested, but checkerboard analysis at pH 4.5 did not meet stringent criteria for synergism.
- CDR1 expression and HMG-CoA reductase activity mirrored the growth-inhibitory pattern: low fluvastatin inhibited HMG-CoA reductase, while intermediate doses inhibited it less. UPC2 induction was 1.53 ± 0.28 at 0.5 μM and 1.69 ± 0.24 at 20 μM, not a significant increase.
- Serum fluvastatin in hypercholesterolemia patients is 2–4 μM, a range with no expected fungistatic or fungicidal action at physiological pH, where the effective concentration is >12.5 μM; at vaginal pH 3.8–4.5, low doses may reduce *C. albicans* survival.
Methods
- Growth assays used clinical *C. albicans* isolates in synthetic medium pH-adjusted with 0.1 M sodium phosphate buffer, microtiter broth dilution, 40 h at 37°C, and OD620; MIC was defined as >50% reduction in OD620 versus control.
- CDR1 expression was monitored with reporter strain CaSA1 expressing GFP under the CDR1 promoter; HMG-CoA reductase activity was measured in ATCC10231 crude extracts by NADPH oxidation at 340 nm, normalized to protein, with averages and standard deviations from 3 independent experiments.
- UPC2 expression was assayed by quantitative reverse transcriptase PCR with PMA1 and 16S RNA controls at 50 ng/μL template, with averages and standard errors from three independent experiments.
Limitations
- Stated: the low-dose sensitizing effects of fluvastatin did not meet stringent criteria for synergism, and further studies are required to fully explain fluvastatin resistance in the intermediate concentration range.
- Evident: the abstract reports the intermediate range as 1–10 mM, while the Results report 1–10 μM, an internal inconsistency in the text.
- Evident: no in vivo vaginal infection model or clinical outcome data are presented, so the therapeutic implications for vaginal *C. albicans* infections remain hypothesis-generating.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 20 cited sources checked · 0 supported · 0 flagged
- Findingreasoning
In the intermediate concentration range of 1-10 μM, FS does not induce drug resistance mechanisms in C. albicans.
“In the intermediate concentration range of 1–10 μM, FS does not induce drug resistance mechanisms.”
Quote in the paperSubstantial claim - Findingown data
At pH 7.0, FS exhibits a simple dose-response correlation against C. albicans.
“While at a pH of 7.0 FS, it exhibits a simple dose/response correlation, the situation at pH 4.5 is different.”
Quote in the paperSubstantial claim - Findingown data
FS-induced changes in CDR1 gene expression are a mirror image of the drug's growth inhibitory effect.
“The FS-induced changes in CDR1 gene expression are a mirror image of the drug's growth inhibitory effect (Figure 2(a)).”
Quote in the paperSubstantial claim - Findingown data
In all eight clinical isolates of C. albicans tested, addition of 0.5 mM FS lowered the MIC for fluconazole by at least a factor of four.
“The fluconazole sensitivity of eight clinical isolates of C. albicans was assayed in the presence and absence of 0.5 mM FS.”
- Also stated in: § 3.1. Inhibition of C. albicans Growth by FS Is Dependent on Environmental pH · plain
“In all strains tested, the addition of FS lowered the MIC for fluconazole by at least a factor of four.”
Quote in the paperSubstantial claim - Also stated in: § 3.1. Inhibition of C. albicans Growth by FS Is Dependent on Environmental pH · plain
- Findingown data
Fluvastatin (FS) has an inhibitory effect on the growth of Candida albicans that is dependent on the pH of the medium.
“The cholesterol-lowering drug fluvastatin (FS) has an inhibitory effect on the growth of the pathogenic yeast Candida albicans that is dependent on the pH of the medium.”
Quote in the paperSubstantial claim
- Findingcitation
The low-dose sensitizing effects of FS did not meet the stringent criteria for synergism as put forward by White and coworkers.
“However the low-dose sensitizing effects of FS did not meet the stringent criteria for synergism as put forward by White and coworkers [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] 1996, Antimicrobial Agents and Chemotherapy source
Not checked in the free run.
- Findingown data
The low dose/low pH inhibitory effect of FS can be exploited to sensitize C. albicans to the action of fluconazole.
“The low dose/low pH inhibitory effect of FS can be exploited to sensitize C. albicans to the action of a common antifungal drug, fluconazole (Figure 1(b)).”
Quote in the paperSubstantial claim - Findingown data
Of six statins examined, FS was the only drug exhibiting a nonlinear dose response.
“Of the 6 statins examined in this study (Atorvastatin, Fluvastatin, Lovastatin, Mevastatin, Pravastatin, Simvastatin), FS was the only drug exhibiting a nonlinear dose response.”
Quote in the paperSubstantial claim - Findingown data
The effective concentration of FS at physiological pH is >12.5 μM.
“No fungistatic or fungicidal action of FS can be expected in this range, as the effective concentration of FS at physiological pH is >12.5 μM.”
Quote in the paperSubstantial claim - Premisecitation
The antifungal action of FS is synergistic with the action of other antifungal drugs.
“Inhibition of sterol synthesis by fluvastatin has an antifungal effect on the opportunistic yeast pathogen Candida albicans and at high concentrations; the antifungal action of FS is synergistic with the action of other antifungal drugs [2, 3].”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
FS has an antifungal effect on Candida albicans at high concentrations.
“Inhibition of sterol synthesis by fluvastatin has an antifungal effect on the opportunistic yeast pathogen Candida albicans and at high concentrations; the antifungal action of FS is synergistic with the action of other antifungal drugs [2, 3].”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Intracellular accumulation of FS leads to inhibition of ergosterol biosynthesis.
“Inside the cell, FS gets trapped by deprotonation at the higher intracellular pH, leading to an intracellular accumulation with subsequent inhibition of ergosterol biosynthesis.”
Quote in the paperSubstantial claim - Interpretationown data
At the low pH of the vagina (pH 3.8 to 4.5), low doses of FS are sufficient to reduce C. albicans survival.
“However, at the low pH of the vagina (pH 3.8 to 4.5) low doses of FS are sufficient to reduce C. albicans survival.”
Quote in the paperSubstantial claim- Rests on an assumption: The pH of the vagina is between 3.8 and 4.5.
- Premisecitation
Combination drug therapy against C. albicans in which FS is combined with azole drugs seems impractical due to the high concentrations of FS required for an inhibitory effect at physiological pH.
“However, a combination drug therapy against C. albicans in which FS is combined with the commonly prescribed azole drugs seems impractical due to the high concentrations of FS required for an inhibitory effect at physiological pH [2, 3].”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
The low-dose growth-inhibitory action of FS at low pH can be understood by the previously demonstrated pH dependency of FS uptake across biological membranes.
“The low-dose growth-inhibitory action of FS at low pH values can be understood in light of the previously demonstrated pH dependency of FS uptake across biological membranes [4].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] source
Not checked in the free run.
- Premisecitation
In patients taking FS for hypercholesterolemia, the serum concentration of FS falls into the intermediate range of 2-4 μM.
“In patients taking FS for the treatment of hypercholesterolemia, the serum concentration of FS falls into the intermediate range of 2–4 μM [14].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] 2001, Journal of Cardiovascular Pharmacology and Therapeutics source
Not checked in the free run.
- Premisecitation
FS uptake into cells is dependent on pH.
“FS uptake into cells is dependent on pH.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] source
Not checked in the free run.
- Interpretationreasoning
At low pH, uncharged FS molecules enter C. albicans cells by diffusion through the membrane.
“At a low pH, the uncharged FS molecules enter the cell by diffusion though the membrane.”
Quote in the paperSubstantial claim - Premisecitation
The uncharged protonated form of FS is taken up more readily than the charged molecule at serum pH.
“The uncharged protonated form of FS in the acidic pH of the intestine is taken up more readily that the charged molecule is present at serum pH [4].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] source
Not checked in the free run.
- Interpretationown data
No fungistatic or fungicidal action of FS can be expected at serum concentrations of 2-4 μM, because the effective concentration of FS at physiological pH is >12.5 μM.
“No fungistatic or fungicidal action of FS can be expected in this range, as the effective concentration of FS at physiological pH is >12.5 μM.”
Quote in the paperSubstantial claim
- May combine two claims. 10
- Classified as probably not a substantial claim. 7
May combine two claims.
Findingown dataInduction of UPC2 is detectable at low FS concentrations (factor 1.53 +/− 0.28 at 0.5 μM), indicating that FS has a physiological effect in this range.
“Induction of the major steroid synthesis regulator UPC2 [10], as determined by qPCR, is detectable at low FS concentrations (factor 1.53 +/− 0.28 at 0.5 μM), indicating that FS indeed has a physiological effect in this range.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] source
Not checked in the free run.
May combine two claims.
Findingown dataA low dose of FS inhibits C. albicans HMG-CoA reductase, while an intermediate dose inhibits the enzyme significantly less.
“While a low dose of FS inhibits C. albicans HMG-CoA reductase, the intermediate dose inhibits the enzyme significantly less (Figure 2(b)).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataUPC2 induction does not increase significantly with escalating FS concentrations (factor 1.69 +/− 0.24 at 20 μM) and thus cannot explain an adaptive response at intermediate concentrations.
“However, UPC2 induction does not increase significantly with escalating FS concentrations (factor 1.69 +/− 0.24 at 20 μM) and can thus not explain an adaptive response at intermediate concentrations.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThere was no change in cell shape or size upon exposure of C. albicans to FS.
“There was no change in cell shape or size upon exposure to FS (data not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAt pH 4.5, FS inhibits C. albicans growth at low (0.5-1.0 μM) and high (>10 μM) concentrations, but not at intermediate concentrations (1-10 μM).
“Growth inhibition can be observed at low (0.5–1.0 μM) and high (>10 μM) concentrations, but not in the intermediate concentration range of 1–10 μM.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
InterpretationreasoningThis response would lead to adequate production of ergosterol and to a lowering of intracellular stress in the presence of FS.
“This then would lead to adequate production of ergosterol and to a lowering of intracellular stress in the presence of FS.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationBoth azoles and statins inhibit the synthesis of the major fungal membrane lipid ergosterol.
“An azole drug was chosen for the analysis because both azoles and statins inhibit the synthesis of the major fungal membrane lipid ergosterol.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
InterpretationcitationIf a certain level of inhibition is exceeded, the cell might respond by inducing the activity of the steroid synthesis pathway, apparently by a UPC2-independent mechanism.
“If a certain level of inhibition is exceeded, the cell might respond by inducing the activity of the steroid synthesis pathway [10, 13], apparently by a UPC2-independent mechanism.”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationStatins inhibit an early step in ergosterol synthesis, the reduction of HMG-CoA.
“While the statins inhibit an early step, the reduction of the steroid precursor hydroxymethylglutaryl-CoA (HMG-CoA), azoles inhibit a later enzymatic step, the demethylation of 14 α-lanosterol [11].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFluvastatin is a widely prescribed inhibitor of HMG-CoA reductase, the key enzyme in sterol biosynthesis.
“Fluvastatin (FS) is a widely prescribed inhibitor of HMG-CoA reductase, the key enzyme in sterol biosynthesis [1].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationAzoles inhibit a later step in ergosterol synthesis, the demethylation of 14 α-lanosterol.
“While the statins inhibit an early step, the reduction of the steroid precursor hydroxymethylglutaryl-CoA (HMG-CoA), azoles inhibit a later enzymatic step, the demethylation of 14 α-lanosterol [11].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationThe expression of the drug exporting pump Cdr1p increases after exposure to a variety of stress factors and is considered a useful reporter for intracellular stress.
“The expression of the drug exporting pump Cdr1p increases after exposure to a variety of stress factors and is considered a useful reporter for intracellular stress [8].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] source
Not checked in the free run.
May combine two claims.
InterpretationreasoningInside the cell, FS gets trapped by deprotonation at the higher intracellular pH, leading to intracellular accumulation.
“Inside the cell, FS gets trapped by deprotonation at the higher intracellular pH, leading to an intracellular accumulation with subsequent inhibition of ergosterol biosynthesis.”
Quote in the paperSubstantial claim- Rests on an assumption: The intracellular pH of C. albicans is higher than the low extracellular pH.
May combine two claims.
InterpretationcitationThe protonated uncharged FS molecule has better access to the yeast cytoplasm than the charged molecule and thus can inhibit growth at lower concentrations.
“We propose that the protonated uncharged FS molecule has better access to the yeast cytoplasm than the charged molecule and thus can inhibit growth at lower concentrations.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Fluvastatin has a pKa of 5.5 and is ionized at physiological pH 7.4.
“Because of its pKa of 5.5, FS is ionized at the physiological pH of 7.4.”
The paper relies on this without support.
The pH of the vagina is between 3.8 and 4.5.
“However, at the low pH of the vagina (pH 3.8 to 4.5) low doses of FS are sufficient to reduce C. albicans survival.”
The paper relies on this without support.
The intracellular pH of C. albicans is higher than the low extracellular pH.
“Inside the cell, FS gets trapped by deprotonation at the higher intracellular pH”
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?
The antifungal activity of FLV is dependent on the pH of the medium.
“The antifungal activity of FLV is dependent on the pH of the medium [27] .”
From Statins as antifungal agents (2011) · cites this paper as [27]
For fluvastatin, complete inhibition of C. albicans at physiological pH would require around 50 g/ml, while MIC values above 128 g/ml have been described for different Candida species and Cryptococcus neoformans.
“Also for fluvastatin, a potent synthetic statin, complete inhibition of C. albicans at physiological pH would require around 50 g/ml, 32 whilst MIC values above 128 g/ml were described for different Candida species and Cryptococcus neoformans.11”
MIC definition may account for differences; some liquid-culture works defined MIC as the drug dose reducing growth by 50% by optical density, while others defined it as the minimal concentration with no visible growth.
“For comparison purposes, the MIC definition may also account for differences.Some works, normally referring to liquid cultures, described MIC as the drug dose at which growth became reduced by 50%, as witnessed by optical density measurements.32,40 Nevertheless, there are authors that defined MIC as herein applied, i.e. the minimal concentration at which no visible growth occurred.3,21”
Research into azole-statin interactions has attracted renewed interest.
“In this context, studies on the interaction between azoles and statins have gained renewed attention.10,11,27,32,37”
Co-administration of statins may be useful for increasing antifungal efficacy, decreasing toxic azole doses, and possibly obtaining desirable side effects such as tumour-abating properties.
“The co-administration of statins may be useful not only for increasing the efficacy of the antifungal treatment or for decreasing the required doses of toxic azoles, but also for eventually obtaining desirable side effects such as tumour-abating properties.16,32,41”
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.
Fluconazole sensitization dose conflicts with the stated low-dose effect
MajorThe paper presents fluconazole sensitization as exploiting the low-dose FS effect, identified as 0.5-1.0 μM. It then says the fluconazole assay used 0.5 mM FS (500 μM), which falls in its stated high-concentration range instead.
“The fluconazole sensitivity of eight clinical isolates of C. albicans was assayed in the presence and absence of 0.5 mM FS.”
“Growth inhibition can be observed at low (0.5–1.0 μM) and high (>10 μM) concentrations, but not in the intermediate concentration range of 1–10 μM.”
Abstract gives the noninhibitory concentration range in mM rather than μM
MinorThe abstract places the noninhibitory intermediate range at 1-10 mM, whereas the results place it at 1-10 μM-a 1,000-fold difference central to the reported dose response.
“while at intermediate concentrations (1–10 mM), it has no inhibitory effect.”
“Growth inhibition can be observed at low (0.5–1.0 μM) and high (>10 μM) concentrations, but not in the intermediate concentration range of 1–10 μM.”
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“If a certain level of inhibition is exceeded, the cell might respond by inducing the activity of the steroid synthesis pathway [10, 13], apparently by a UPC2-independent mechanism.”
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Dose Dependency of Fluvastatin Pharmacokinetics in Serum Determined by Reversed Phase HPLC
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“It has been observed that statins are beneficial for FLC against For example, fl uvastatin acts synergistically with FLC against Candida species [73–75], including FLC-resistant strains of C. albicans and C. tropicalis [74,76].”
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- Authors
- Schmidt, M., Dzogbeta, S., & Boyer, M. P.
- Affiliations
- Des Moines University (US)
- Corresponding author
- Schmidt, Martin
- ORCID
- Schmidt, Martin
- Venue
- Research Letters in Biochemistry
- Publisher
- Wiley
- Published
- 2009
- Volume
- 2009
- Pages
- 1-4
- ISSN
- 1687-6709 (ISSN-L)
- 1687-6717
- PMC
- PMC3005803
- OpenAlex
- W2095680562
- Cited by
- 7
- References
- 13
- Citations by year
- 2024: 2 · 2020: 1 · 2019: 1 · 2016: 1 · 2012: 1
- FWCI
- 0.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Research Letters in Biochemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Iowa Science Foundation
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- fluvastatin, Candida albicans, pH dependence, antifungal drug interactions, fluconazole, HMG-CoA reductase, sterol biosynthesis, intracellular stress, vaginal candidiasis, statins
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