Mathematical Modeling of Fluconazole Resistance in the Ergosterol Pathway of
            <i>Candida albicans</i>

Yu, Paul Kwong; Moron-Espiritu, Llewelyn Sotto; Lao, Angelyn R.

doi:10.1128/msystems.00691-22

Cited by 3 publications

(2 citation statements)

References 24 publications

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“…Interestingly, we did not observe any difference in ergosterol concentrations for the caspofungin isolates. This is documented in the literature, as only a relationship between the pathway and fluconazole resistance is documented [29,30]. As such, in our study, a significant 65% increase in ergosterol content was observed in the fluconazole-resistant isolates compared to the control, indicating that C. albicans developed a compensatory mechanism by upregulating ergosterol biosynthesis, resulting in a thickening of the cell surface, which makes it harder for the drug to permeate the cell, hence maintaining cell membrane integrity.…”

Section: Discussionsupporting

confidence: 51%

Sequential Induction of Drug Resistance and Characterization of an Initial Candida albicans Drug-Sensitive Isolate

El Hachem,

Fattouh,

Chedraoui

et al. 2024

JoF

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Background: The pathogenic fungus Candida albicans is a leading agent of death in immunocompromised individuals with a growing trend of antifungal resistance. Methods: The purpose is to induce resistance to drugs in a sensitive C. albicans strain followed by whole-genome sequencing to determine mechanisms of resistance. Strains will be assayed for pathogenicity attributes such as ergosterol and chitin content, growth rate, virulence, and biofilm formation. Results: We observed sequential increases in ergosterol and chitin content in fluconazole-resistant isolates by 78% and 44%. Surface thickening prevents the entry of the drug, resulting in resistance. Resistance imposed a fitness trade-off that led to reduced growth rates, biofilm formation, and virulence in our isolates. Sequencing revealed mutations in genes involved in resistance and pathogenicity such as ERG11, CHS3, GSC2, CDR2, CRZ2, and MSH2. We observed an increase in the number of mutations in key genes with a sequential increase in drug-selective pressures as the organism increased its odds of adapting to inhospitable environments. In ALS4, we observed two mutations in the susceptible strain and five mutations in the resistant strain. Conclusion: This is the first study to induce resistance followed by genotypic and phenotypic analysis of isolates to determine mechanisms of drug resistance.

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Section: Discussionsupporting

confidence: 51%

Sequential Induction of Drug Resistance and Characterization of an Initial Candida albicans Drug-Sensitive Isolate

El Hachem,

Fattouh,

Chedraoui

et al. 2024

JoF

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“…albicans increases its virulence mainly by forming hyphae and biofilm. At present, the conventional drugs mainly used for the treatment of C. albicans infection are azole compounds (Yu et al, 2022), such as fluconazole (FLC), nystatin, etc. However, because these drugs can only play a role in inhibiting fungi, they cannot directly kill C. albicans.…”

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confidence: 99%

Cyclometalated iridium(III) complexes combined with fluconazole: antifungal activity against resistant C. albicans

Zhu

et al. 2023

Front. Cell. Infect. Microbiol.

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Candida albicans (C. albicans) is a ubiquitous clinical fungal pathogen. In recent years, combination therapy, a potential treatment method to overcome C. albicans resistance, has gained traction. In this study, we synthesized a series of cyclometalated iridium(III) complexes with the formula [Ir(C-N)2(tpphz)](PF6) (C-N = 2-phenylpyridine (ppy, in Ir1), 2-(2-thienyl)pyridine (thpy, in Ir2), 2-(2,4-difluorophenyl) pyridine (dfppy, in Ir3), tpphz = tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3'''-j]phenazine) and polypyridyl ruthenium(II) complexes with the formula [Ru(N-N)2(tpphz)](PF6)2 (N-N = 2,2'-bipyridine (bpy, in Ru1), 1,10-phenanthroline (phen, in Ru2), 4,7-diphenyl-1,10-phenanthroline (DIP, in Ru3)), and investigated their antifungal activities against drug-resistant C. albicans and their combination with fluconazole (FLC). Of which, the combination of the lead iridium(III) complex Ir2 and FLC showed strong antifungal activity against drug-resistant C. albicans. Mechanism studies have shown that they can inhibit the formation of hyphae and biofilm, damage mitochondrial function and accumulate intracellular ROS. Therefore, iridium(III) complexes combined with FLC can be used as a promising treatment to exert anti-drug-resistant C. albicans activity, in order to improve the treatment efficiency of fungal infection.

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Insights into the antifungal mechanism of Bacillus subtilis cyclic lipopeptide iturin A mediated by potassium ion channel

Yang,

Ji,

Xue

et al. 2024

International Journal of Biological Macromolecules

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Mathematical Modeling of Fluconazole Resistance in the Ergosterol Pathway of Candida albicans

Cited by 3 publications

References 24 publications

Sequential Induction of Drug Resistance and Characterization of an Initial Candida albicans Drug-Sensitive Isolate

Sequential Induction of Drug Resistance and Characterization of an Initial Candida albicans Drug-Sensitive Isolate

Cyclometalated iridium(III) complexes combined with fluconazole: antifungal activity against resistant C. albicans

Insights into the antifungal mechanism of Bacillus subtilis cyclic lipopeptide iturin A mediated by potassium ion channel

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