CoChat
Sign Up
Cited by 16Antifungal resistance and susceptibilityFungal Plant Pathogen ControlFungal Infections and Studies

Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris

Open access
Salama, Ehab A., Elgammal, Yehia, Wijeratne, Aruna, Lanman, Nadia A., Utturkar, Sagar M., Farhangian, Atena, Li, Jianing, Meunier, Brigitte +2 more·2024·Emerging Microbes & Infections
DOI 10.1080/22221751.2024.2322649PMC PMC10911247
Open this paper in CoChat — free accountOpen PDF

Abstract

Candida auris has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, C. auris possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we screened a panel of 727 FDA-approved drugs. We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB’s activity against C. auris. LNP also potentiates the antifungal activity of AmB against other medically important species of Candida and Cryptococcus. Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome bc1). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (∼98%) CFU reduction in the burden of C. auris in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome bc1 inhibitor for combating drug-resistant C. auris infections.

AI snapshot

Written from the paper’s full text.

TL;DR

Screening 727 FDA-approved drugs identified lansoprazole (LNP) as a potentiator of amphotericin B (AmB) against multidrug-resistant *Candida auris*. LNP/AmB showed broad synergy, increased ROS, targeted mitochondrial cytochrome bc1, and reduced *C. auris* kidney burden in mice.

Key findings

  • LNP synergized with AmB against 90% (18/20) of *C. auris* clinical isolates, including AmB-resistant isolates; the two non-synergistic isolates still had AmB MICs reduced to susceptible levels.
  • LNP (40 μg/mL) restored AmB (2 μg/mL) fungicidal activity against resistant *C. auris* within 6 hr, whereas AmB alone did not prevent growth over 24 hr.
  • AmB/LNP increased ROS by 77%, compared with 29% for LNP alone and 32% for AmB alone; PISA identified mitochondrial cytochrome bc1 (complex III) as a potential LNP target.
  • In an immunocompromised mouse model, AmB/LNP reduced *C. auris* kidney burden by 1.7-log (~98%) versus untreated mice and by 1 log (90%) versus AmB alone.

Methods

  • In vitro screening of 727 FDA-approved drugs/clinical molecules against AmB-resistant *C. auris* AR0390, followed by checkerboard MIC assays, time-kill assays, and testing against 20 *C. auris* isolates and other *Candida*/*Cryptococcus* species.
  • Mechanistic analyses included PISA proteomics, RNA-Seq, ROS measurement with H2DCFDA, *S. cerevisiae* growth assays with respiratory mutants and SOD deletions, cytochrome bc1 activity assays, and molecular docking.
  • In vivo efficacy used neutropenic CD-1 mice infected with *C. auris* AR0390 and treated with vehicle, AmB (0.5 mg/kg), LNP (300 mg/kg), or AmB/LNP; kidney CFU burdens were measured.

Limitations

  • Stated: elevated LNP doses were required for in vitro and in vivo synergy; LNP is unstable and yields several metabolites, so the exact active metabolite and its formation remain unknown; comprehensive toxicological studies in mice are needed.
  • Evident: most *C. auris* isolates cannot grow on glycerol or ethanol, so the respiration dependence of LNP activity could not be directly tested in *C. auris*; LNP itself had hardly any direct effect on cytochrome bc1 activity, and lansoprazole sulfide was only a weak inhibitor and did not synergize with AmB.
  • Evident: the in vivo kidney CFU result is described as coming from a single experiment.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1080/22221751.2024.2322649

Cites

63 of 63 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 40 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Eight statistically significant proteins exhibited increased solubility in the presence of LNP.

    “Proteins with increased abundance were excluded, resulting in the identification of eight statistically significant proteins that exhibited increased solubility in the presence of LNP as represented by the ΔSm distribution (Figure 2 and Table S2).”
    Quote in the paperSubstantial claim
  • Findingown data

    LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain, complex III (cytochrome bc1).

    “Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome bc1).”
    Quote in the paperSubstantial claim
  • Findingown data

    LNP demonstrated a synergistic interaction with AmB in 90% (18 out of 20) of Candida auris clinical isolates.

    “Notably, LNP demonstrated a synergistic interaction with AmB in 90% (18 out of 20) of the isolates.”
    Quote in the paperSubstantial claim
  • Findingnone given

    B9J08_005505 is the Candida auris ortholog of the Rieske protein, a member of the cytochrome bc1 complex, encoded by RIP1 in Candida albicans and Saccharomyces cerevisiae.

    “B9J08_005505 is the C. auris ortholog of the Rieske protein, a member of cytochrome bc1 complex, which is encoded by the RIP1 gene in C. albicans and S. cerevisiae.”
    Quote in the paperSubstantial claim
  • Findingown data

    Lansoprazole (LNP) was identified as a potent enhancer of amphotericin B (AmB) activity against Candida auris.

    “We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB’s activity against C. auris.”
    • Also stated in: § Drug library screen identifies LNP as a potentiator of AmB’s antifungal activity · boosted
      “Thus, LNP was identified as a robust potentiator of the antifungal activity of AmB (Figure 1a).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Lansoprazole has a favourable safety and pharmacokinetic profile.
  • Classified as probably not a substantial claim. 30
  • May combine two claims. 30
  • The quote only partly states this claim. 2

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Cytochrome c1 had a high ΔSm value but was excluded as a PISA hit because it also had a high protein abundance value in the LNP-treated sample.

    “In addition, cytochrome c1 had a high ΔSm value but was excluded as a PISA hit because it also had a high protein abundance value in the LNP-treated sample.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    A total of 2631 proteins were identified between the PISA and global proteomics experiments.

    “A total of 2631 proteins were identified between the PISA and global proteomics experiments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (~98%) CFU reduction in the burden of Candida auris in the kidneys.

    “Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (∼98%) CFU reduction in the burden of C. auris in the kidneys.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cytochrome b peptides were not identified in the proteomic experiments, so the PISA analysis could not assess stabilization by LNP treatment.

    “However, cytochrome b peptides were not identified in the proteomic experiments, so the PISA analysis could not assess stabilization by LNP treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In both LNP and lansoprazole sulfide, the imidazole ring forms a T-shape stacking with Y279 and the pyridine ring forms pi-pi and halogen-pi interactions with F296.

    “Similar in both compounds, the imidazole ring forms a T-shape stacking with the side chain of Y279 (Figure 5a) and the pyridine ring forms pi-pi and halogen-pi interactions with F296.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Similar results were observed for C. albicans SC5314 strain growth in the presence of glucose versus glycerol as a carbon source.

    “Similar results were observed for the C. albicans SC5314 strain growth in the presence of glucose versus glycerol as a carbon source (Fig. S1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LNP exhibited a synergistic relationship with AmB against 90% of the tested isolates and restored the fungicidal capability of AmB within 6 hr.

    “LNP exhibited a synergistic relationship with AmB against 90% of the tested isolates and restored the fungicidal capability of AmB within 6 hr.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The parent strain and F129L were fully inhibited by atovaquone, while L275F, F278A and Y279C were resistant.

    “The parent strain and F129L were fully inhibited by atovaquone, while L275F, F278A and Y279C were resistant.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both LNP and lansoprazole sulfide adopt similar extended poses mainly stabilized by hydrophobic contacts in the pocket.

    “Both LNP and Lansoprazole sulfide adopt similar extended poses, mainly stabilized by hydrophobic contacts in the pocket.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The AmB/LNP combination led to a 77% increase in ROS levels, significantly higher than fungal cells treated with either LNP or AmB alone.

    “As expected, the AmB/LNP combination led to a 77% increase in ROS levels, significantly higher than fungal cells treated with either LNP or AmB alone (Figure 3b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both Δsod1 and Δsod2 Saccharomyces cerevisiae mutants showed high sensitivity to LNP with reduced growth by 90% and 89%, respectively, compared to the parent strain AD1-9.

    “Both mutants showed high sensitivity to LNP with reduced growth by 90% and 89%, respectively, as compared to the parent strain AD1-9 (Figure 3c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 48 hr, the rho+ Saccharomyces cerevisiae (in YPD and YPEtOH) was inhibited by ~95%, while the rho° was inhibited by 40%.

    “At 48 hr, the rho+ (in YPD and YPEtOH) was inhibited by ∼95%, while the rho° was inhibited by 40% (Figure 4a and 4b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two out of the three upregulated genes in the LNP-treated group were superoxide dismutase homologues (SOD1 and SOD4) and the third was the multidrug transporter CDR1.

    “Two out of the three upregulated genes were found to be superoxide dismutase homologues (SOD1 and SOD4) and the third gene was the multidrug transporter, CDR1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LNP at 300 mg/kg significantly enhanced the activity of AmB at 0.5 mg/kg in a murine model, reducing kidney fungal burden by 1.7-log (98%) compared to untreated mice and by one log (90%) compared to the AmB-treated group.

    “LNP (300 mg/kg) significantly enhanced the activity of AmB (0.5 mg/kg) as the AmB/LNP combination reduced the fungal burden in the kidneys by 1.7-log (98%) reduction compared to untreated mice and by one log (90%) reduction compared to the AmB-treated group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The docking score to bovine bc1 with UHDBT is −8.2 kcal/mol, which is 2.6 kcal/mol higher than that of the C. albicans cytochrome bc1 structure.

    “the docking score to the bovine bc1 with UHDBT (PDB ID: 1SQV) structure is –8.2 kcal/mol, which is 2.6 kcal/mol higher than that of the C. albicans cytochrome bc1 structure (Figure 5b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LNP shows a slightly more favourable docking pose to C. albicans cytochrome bc1 with a Glide XP score of −10.8 kcal/mol, while lansoprazole sulfide has a score of −10.4.

    “LNP shows a slightly more favourable pose with a Glide XP score of −10.8 kcal/mol (Figure 5a) while this score is −10.4 for Lansoprazole sulfide.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Rotenone can improve the activity of AmB but also can block further synergy between AmB and either LNP or antimycin A.

    “We confirmed that rotenone can improve the activity of AmB but also can block further synergy between AmB with either LNP or antimycin A.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The up- and downregulated genes after treatment with AmB or AmB/LNP were extensive and driven by DNA damage.

    “The up and downregulated genes after treatment with either AmB (0.5 µg/mL) or AmB/LNP (0.5/30 µg/mL) were extensive and driven by DNA damage”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Molecular docking analysis showed that LNP and four metabolites could possibly bind to the Qo site of cytochrome bc1 and that small changes in drug structure could alter binding to the target.

    “Molecular docking analysis showed that LNP and four metabolites could possibly bind to Qo site of cytochrome bc1 and that small changes in the drug structure could alter its binding to the target.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The mutated residues are located in the Qo site formed by cytochrome b interacting with the Rieske protein to create the ubiquinol oxidation site within the cytochrome bc1 complex.

  • May combine two claims.

    Findingown data

    LNP generates ROS in C. auris, and ROS production considerably increased when LNP was combined with AmB.

    “Here, we showed that LNP generates ROS in C. auris and how the production of ROS considerably increased when LNP was combined with AmB.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The AmB/LNP combination was well tolerated, with no signs of toxicity observed in any of the treated mice.

    “the AmB/LNP combination was well tolerated, with no signs of toxicity observed in any of the treated mice”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A minor but growing resistance (1-7%) has been reported towards echinocandins in Candida auris.

    “However, a minor but alarmingly growing resistance (1-7%) has been reported towards the third class (echinocandins) [10,11].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Lockhart SR, Etienne KA, Vallabhaneni S, et al. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis. 2017 Jan 15; 64(2): 134– 140. doi: 10.1093/cid/ciw691 27988485 PMC5215215 source

      Not checked in the free run.

    • cites [11] Chowdhary A, Prakash A, Sharma C, et al. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009–17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J Antimicrob Chemoth. 2018 Apr; 73(4): 891– 899. doi: 10.1093/jac/dkx480 29325167 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    AmB/LNP therapy potentially interferes with fungal respiration, leading to increased oxidative pressure.

    “The AmB/LNP therapy was recognized as potentially interfering with fungal respiration, leading to increased oxidative pressure.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Combination therapy has proven to be an effective approach in overcoming antifungal drug resistance.

    “Combination therapy has proven to be an effective approach in overcoming antifungal drug resistance, significantly contributing to preserving the existing arsenal of antimicrobial agents, reducing treatment duration, and mitigating drug toxicity [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Hill JA, Cowen LE. Using combination therapy to thwart drug resistance. Future Microbiol. 2015; 10(11): 1719– 1726. doi: 10.2217/fmb.15.68 26597425 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Mitochondrial complex III (cytochrome bc1) was previously identified as a target of LNP in Mycobacterium tuberculosis.

    “Among these potential targets, we focused on mitochondrial complex III, also referred to as cytochrome bc1, because the complex was previously identified as a target of LNP in Mycobacterium tuberculosis [44].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Rybniker J, Vocat A, Sala C, et al. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1. Nat Commun. 2015 Jul 9; 6: 7659. doi: 10.1038/ncomms8659 26158909 PMC4510652 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Combination therapy is an alternative approach to overcoming growing microbial infection resistance.

    “Combination therapy is an alternative approach to overcoming the growing microbial infection resistance [23,24].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Shekhar-Guturja T, Gunaherath GM, Wijeratne EM, et al. Dual action antifungal small molecule modulates multidrug efflux and TOR signaling. Nat Chem Biol. 2016 Oct; 12(10): 867– 875. doi: 10.1038/nchembio.2165 27571477 PMC5030160 source

      Not checked in the free run.

    • cites [24] Eldesouky HE, Mayhoub A, Hazbun TR, et al. Reversal of azole resistance in Candida albicans by Sulfa antibacterial drugs. Antimicrob Agents Chemother. 2018 Mar; 62(3). doi: 10.1128/AAC.00701-17 PMC5826110 29263071 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Study design and conductown data

    RNA-Seq analysis was performed in triplicates.

    “Exponential C. auris AR0390 in RPMI 1640 medium were treated with DMSO (control), AmB (0.5 µg/mL), LNP (30 µg/mL), or the combination of AmB/LNP in triplicates for 3 hr at 35 °C.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The statistical analysis was carried out using a one-way ANOVA of Dunnett's test for multiple comparisons using GraphPad Prism 8.

    “The number of biological replicates is noted in each experiment, and the statistical analysis was carried out using a one-way ANOVA of Dunnett’s test for multiple comparisons using GraphPad Prism 8 (GraphPad Software, La Jolla, CA) unless otherwise noted.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The experiments were repeated at least twice, and the data was averaged.

    “The experiments were repeated at least twice, and the data was averaged.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metal ion homeostasis is crucial in minimizing ROS formation.

    “Consistent with the notion of LNP-mediated oxidative damage, the SODs are antioxidant enzymes that detoxify ROS [48], and metal ion homeostasis is crucial in minimizing ROS formation [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Temple MD, Perrone GG, Dawes IW. Complex cellular responses to reactive oxygen species. Trends Cell Biol. 2005 Jun; 15(6): 319– 326. doi: 10.1016/j.tcb.2005.04.003 15953550 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The effect of LNP started to fade after 72 hr potentially due to the instability of LNP in the culture media.

    “The effect started to fade after 72 hr potentially due to the instability of LNP in the culture media.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The S. cerevisiae cytochrome b mutants F129L, L275F, F278A and Y279C were previously generated using mitochondrial transformation.

    “These mutants were previously generated using the mitochondrial transformation technique [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Hill P, Kessl J, Fisher N, et al. Recapitulation in Saccharomyces cerevisiae of cytochrome b mutations conferring resistance to atovaquone in pneumocystis jiroveci. Antimicrob Agents Chemother. 2003 Sep; 47(9): 2725– 2731. doi: 10.1128/AAC.47.9.2725-2731.2003 12936966 PMC182622 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    Microdilution checkerboard assays were utilized, and the ΣFICI was calculated and interpreted as previously described.

    “To evaluate the in vitro effectiveness of the AmB/LNP combination against a variety of Candida species, microdilution checkerboard assays were utilized, and the ΣFICI was calculated and interpreted as previously described [26,27].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Gu W, Guo D, Zhang L, et al. The synergistic effect of azoles and fluoxetine against resistant Candida albicans strains is attributed to attenuating fungal virulence. Antimicrob Agents Chemother. 2016 Oct; 60(10): 6179– 6188. doi: 10.1128/AAC.03046-15 27503639 PMC5038273 source

      Not checked in the free run.

    • cites [27] Eldesouky HE, Salama EA, Hazbun TR, et al. Ospemifene displays broad-spectrum synergistic interactions with itraconazole through potent interference with fungal efflux activities. Sci Rep. 2020 Apr 8; 10(1): 6089. doi: 10.1038/s41598-020-62976-y 32269301 PMC7142066 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Superoxide dismutases (SODs) are antioxidant enzymes that detoxify reactive oxygen species (ROS).

    “Consistent with the notion of LNP-mediated oxidative damage, the SODs are antioxidant enzymes that detoxify ROS [48], and metal ion homeostasis is crucial in minimizing ROS formation [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Dantas Ada S, Day A, Ikeh M, et al. Oxidative stress responses in the human fungal pathogen, Candida albicans. Biomolecules. 2015 Feb 25; 5(1): 142– 165. doi: 10.3390/biom5010142 25723552 PMC4384116 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The MICs of AmB and LNP against yeast isolates were identified using the CLSI M27-A3 guidelines.

    “The MICs of AmB and LNP against yeast isolates were identified using the CLSI M27-A3 guidelines [25].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] CLSI. Reference method for broth dilution antifungal susceptibility testing of yeasts. In: 4th ed. CLSI standard M27. Wayne, PA: Clinical and Laboratory Standards Institute; 2017.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The Benjamini-Hochberg method was used to adjust the P-values for multiple testing.

    “The Benjamini-Hochberg method was used to adjust the P-values for multiple testing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The PISA assay was performed with biological triplicates.

    “We performed the PISA assay with biological triplicates to identify LNP’s target in C. auris, as previously described [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Gaetani M, Sabatier P, Saei AA, et al. Proteome integral solubility alteration: A high-throughput proteomics assay for target deconvolution. J Proteome Res. 2019 Nov 1; 18(11): 4027– 4037. doi: 10.1021/acs.jproteome.9b00500 31545609 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The measurements were repeated twice, and the data was averaged.

    “The measurements were repeated twice, and the data was averaged.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Another cytochrome bc1 inhibitor, Inz-5, alters the configuration of the Rieske head domain in mitochondrial cytochrome bc1, demonstrating the targetability of that complex.

    “a recent study showed that another cytochrome bc1 inhibitor (Inz-5) alters the configuration of the Rieske head domain in mitochondrial cytochrome bc1, demonstrating the targetability of that complex [57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Di Trani JM, Liu Z, Whitesell L, et al. Rieske head domain dynamics and indazole-derivative inhibition of Candida albicans complex III. Structure. 2022 Jan 6; 30(1): 129– 138 e4. doi: 10.1016/j.str.2021.08.006 34525326 source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationown data

    The additional hydrogen bond may explain the different docking scores between LNP and lansoprazole sulfide.

    “which may explain the different docking scores.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Antifungal combination therapy has potential to treat multidrug- and pandrug-resistant C. auris, as previously reported.

    “The potential of antifungal combination therapy to treat multidrug- and pandrug-resistant C. auris has been previously reported [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] O'Brien B, Liang J, Chaturvedi S, et al. Pan-resistant Candida auris: New York subcluster susceptible to antifungal combinations. Lancet Microbe. 2020 Sep; 1(5): e193– e194. doi: 10.1016/S2666-5247(20)30090-2 35544199 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the presence of a high concentration of rotenone, the electron transport chain is disrupted at complex I, which prevents cytochrome bc1 inhibitors such as antimycin A from generating more ROS.

    “The combination of inhibitors strongly supports that in the presence of a high concentration of rotenone, the electron transport chain is disrupted at an earlier step (complex I), which prevents cytochrome bc1 inhibitors, such as antimycin A, from generating more ROS.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Earlier studies pointed to a correlation between withstanding oxidative stress and AmB resistance in other fungal species.

    “earlier studies pointed to a correlation between withstanding oxidative stress and AmB resistance in other fungal species [58].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Sokol-Anderson M, Sligh JE Jr., Elberg S, et al. Role of cell defense against oxidative damage in the resistance of Candida albicans to the killing effect of amphotericin B. Antimicrob Agents Chemother. 1988 May; 32(5): 702– 705. doi: 10.1128/AAC.32.5.702 3293525 PMC172255 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Cytochrome bc1 is a crucial component of cellular respiration.

    “The cytochrome bc1 is a crucial component of cellular respiration [61]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Musso L, Fabbrini A, Dallavalle S. Natural compound-derived cytochrome bc1 complex inhibitors as antifungal agents. Molecules. 2020 Oct 7; 25(19): 1– 28. PMC7583968 33036496 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other FDA-approved medications, like atovaquone, target plasmodial cytochrome bc1 safely, which validates cytochrome bc1 as a suitable drug target.

    “other FDA-approved medications, like atovaquone, target plasmodial cytochrome bc1 safely, which validates cytochrome bc1 as a suitable drug target [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Simm C, Luan CH, Weiss E, et al. High-throughput screen for identifying small molecules that target fungal zinc homeostasis. PLoS One. 2011; 6(9): e25136. doi: 10.1371/journal.pone.0025136 21980385 PMC3182986 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cytochrome bc1 was identified as a target for a LNP metabolite in M. tuberculosis.

    “Cytochrome bc1 was also identified as a target for a LNP metabolite in M. tuberculosis, which further supported the hypothesis that cytochrome bc1 is a potential target in C. auris [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Rybniker J, Vocat A, Sala C, et al. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1. Nat Commun. 2015 Jul 9; 6: 7659. doi: 10.1038/ncomms8659 26158909 PMC4510652 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    LNP might target fungal cytochrome bc1 through other metabolites, possibly aided by AmB treatment.

    “LNP might target the fungal cytochrome bc1 through other metabolites (which may be aided by the AmB treatment).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: LNP is an unstable compound that yields several metabolites.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The role of oxidative damage as a secondary mode of action for AmB has been highlighted in several reports.

    “The role of oxidative damage as a secondary mode of action for AmB has been highlighted in several reports [56].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Mesa-Arango AC, Trevijano-Contador N, Roman E, et al. The production of reactive oxygen species is a universal action mechanism of Amphotericin B against pathogenic yeasts and contributes to the fungicidal effect of this drug. Antimicrob Agents Chemother. 2014 Nov; 58(11): 6627– 6638. doi: 10.1128/AAC.03570-14 25155595 PMC4249417 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The evidence leads to the central hypothesis that fungal cytochrome bc1 is the potential target by which LNP works synergistically with AmB.

    “the evidence leads us to our central hypothesis that the fungal cytochrome bc1 is the potential target by which LNP works synergistically with AmB (Figure 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    This research highlights the importance of cytochrome bc1 as a potential antifungal target, emphasizing its role in augmenting the antifungal effectiveness of amphotericin B particularly against drug-resistant C. auris.

    “This research highlights the importance of cytochrome bc1 as a potential antifungal target, emphasizing its role in augmenting the antifungal effectiveness of amphotericin B particularly against drug-resistant C. auris.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some inhibitors of cytochrome bc1 were deemed to be toxic to human cells.

    “some inhibitors to cytochrome bc1 were deemed to be toxic to human cells [63].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Guidarelli A, Brambilla L, Rota C, et al. The respiratory-chain poison antimycin A promotes the formation of DNA single-strand breaks and reduces toxicity in U937 cells exposed to t-butylhydroperoxide. Biochem J. 1996 Jul 15; 317(Pt 2): 371– 375. doi: 10.1042/bj3170371 8713060 PMC1217497 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Previous studies reported that targeting fungal cytochrome bc1 disrupts the ability of C. albicans to tolerate antifungal drugs, sensitizes C. albicans to macrophages, and impairs the virulence of C. albicans in mice.

    “previous studies reported that targeting fungal cytochrome bc1 disrupts the ability of C. albicans to tolerate exposure to antifungal drugs, sensitizes C. albicans to macrophages, and, most importantly, impairs the virulence of C. albicans in mice [62].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Vincent BM, Langlois JB, Srinivas R, et al. A fungal-selective cytochrome bc(1) inhibitor impairs virulence and prevents the evolution of drug resistance. Cell Chem Biol. 2016 Aug 18; 23(8): 978– 991. doi: 10.1016/j.chembiol.2016.06.016 27524297 PMC5159300 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous research highlighted the importance of cytochrome bc1 as a potential antifungal drug target.

    “Previous research highlighted the importance of cytochrome bc1 as a potential antifungal drug target [61,62].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [61] Musso L, Fabbrini A, Dallavalle S. Natural compound-derived cytochrome bc1 complex inhibitors as antifungal agents. Molecules. 2020 Oct 7; 25(19): 1– 28. PMC7583968 33036496 source

      Not checked in the free run.

    • cites [62] Vincent BM, Langlois JB, Srinivas R, et al. A fungal-selective cytochrome bc(1) inhibitor impairs virulence and prevents the evolution of drug resistance. Cell Chem Biol. 2016 Aug 18; 23(8): 978– 991. doi: 10.1016/j.chembiol.2016.06.016 27524297 PMC5159300 source

      Not checked in the free run.

53 of 53

  • The paper relies on this without support.

    Resistance to amphotericin B is rare among Candida species and most fungal pathogens.

    “Resistance to AmB is rare among Candida species and most fungal pathogens.”

  • The paper relies on this without support.

    Lansoprazole has a favourable safety and pharmacokinetic profile.

    “Among all identified hits, LNP was selected for further investigation in this study due to its favourable safety and pharmacokinetic profile.”

  • The paper relies on this without support.

    The mutated residues are located in the Qo site formed by cytochrome b interacting with the Rieske protein to create the ubiquinol oxidation site within the cytochrome bc1 complex.

    “The mutated residues are located in the so-called Qo site formed by cytochrome b interacting with the Rieske protein to create the ubiquinol oxidation site within the cytochrome bc1 complex.”

  • The paper relies on this without support.

    LNP is an unstable compound that yields several metabolites.

    “LNP is an unstable compound, yielding several metabolites”
4 of 4

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?

  • Lansoprazole can synergize with amphotericin B by inhibiting cytochrome bc1 in C. auris, consistent with our data for AR387 and R1 yielding fractional inhibitory concentration index values of 0.625 and 0.75, respectively.

    “Lansoprazole can synergize with AMB by inhibiting cytochrome bc1 in C. auris35, which is consistent with our data for AR387 and R1, yielding fractional inhibitory concentration index (FICI) values of 0.625 and 0.75, respectively.”

    From Candida auris skin tropism and antifungal resistance are mediated by carbonic anhydrase Nce103 (2025) · cites this paper as [35]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. CLSI. Reference method for broth dilution antifungal susceptibility testing of yeasts. In: 4th ed. CLSI standard M27. Wayne, PA: Clinical and Laboratory Standards Institute; 2017.

Cited by

Sorted by citations

Related

Authors
Salama, E. A., Elgammal, Y., Wijeratne, A., Lanman, N. A., Utturkar, S. M., Farhangian, A., Li, J., Meunier, B., Hazbun, T. R., & Seleem, M. N.
Affiliations
  • Virginia–Maryland College of Veterinary Medicine (US)
  • Indiana University Indianapolis (US)
  • Purdue University West Lafayette (US)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Hazbun, Tony R.
  • Seleem, Mohamed N.
ORCID
Venue
Emerging Microbes & Infections
Publisher
Informa UK Limited
Published
2024-03-03
Volume
13
Issue
1
Pages
2322649-2322649
ISSN
2222-1751 (ISSN-L)
DOI
10.1080/22221751.2024.2322649
PMC
PMC10911247
OpenAlex
W4392344298
Semantic Scholar
56f5c84cd3675269c0a1ddd9df08010b4db032db
Cited by
16
References
61
Citations by year
2026: 4 · 2025: 6 · 2024: 6
FWCI
5.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Emerging Microbes & Infections (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • HAL (submittedVersion, cc-by-nc)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Institutes of Health (P30 CA023168)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
  • Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Keywords
lansoprazole, amphotericin B, Candida auris, multidrug resistance, antifungal synergy, proton pump inhibitors, cytochrome bc1 complex, mitochondrial respiratory chain, oxidative stress, drug repurposing, Cryptococcus, immunocompromised mouse model
MeSH terms
Candida auris, Amphotericin B, Animals, Antifungal Agents, Candidiasis, Cytochromes, Respiration, Mice, Lansoprazole

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review