Molecular mechanism of fluconazole resistance and pathogenicity attributes of Lebanese Candida albicans hospital isolates

Fattouh, Nour; Hdayed, Dana; Geukgeuzian, Geovanni; Tokajian, Sima; Khalaf, Roy A.

doi:10.1016/j.fgb.2021.103575

Cited by 11 publications

(15 citation statements)

References 36 publications

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“…Antifungal activity screening of target molecules was performed against C. albicans , [30] A. niger [31] and A. Flavus pathogens, by employing Agar diffusion method [32] at 10 μg/mL using Fluconozole [23] as reference drug. Zone of inhibition values were expressed in mm are shown in Table 3.…”

Section: Resultsmentioning

confidence: 99%

“…1,2,3-triazole is stable to enzymatic degradation, hydrolysis, oxidation and reduction. [21] Ciprofloxacin [22] is a broad-spectrum antibiotic received the complaint of antibiotic resistance and Fluconazole [23] as well is widely recommended drug to treat broad spectrum fungal infections becoming insensitive. Therefore, there is huge need to synthesize new antimicrobial drug candidates.…”

Section: Introductionmentioning

confidence: 99%

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Bis 1, 2, 3‐ Triazoles Linked Deoxybenzoin Hybrids as Antimicrobial Agents: Synthesis, In Vitro and In Silico Screening

Aitha

Thumma²,

Ambala

et al. 2023

ChemistrySelect

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A series of new deoxybenzoin based bis 1,2,3‐triazole analogues were synthesized and reported in the present communication. Synthesis of analogues were accomplished by a convenient 3 step protocol incorporating Friedel craft acetylation, propargylation and copper‐catalyzed click chemistry in final step to afford 1,2,3‐triazole moiety. The title compounds were screened for antimicrobial activity against two gram positive bacteria viz. S. aureus, B. cereus and two gram negative bacteria viz. E. coli, P. aeruginosa, and three fungus viz. C. albicans, A. niger, A. flavus strains. Compound containing 4‐fluoro substitution (7a) showed slightly superior in‐vitro antimicrobial activity than reference drugs Ciprofloxacin and Fluconazole. SAR of developed hybrids with reference to antimicrobial activity was predicted and presented. In‐silico bioactivity is investigated by molecular docking studies against the crystal structures of glucosamine‐6‐phospate synthase (PDB ID: 2VF5) and secreted aspartic proteinase (PDB ID: 2QZW) which endorsed good binding interactions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bis 1, 2, 3‐ Triazoles Linked Deoxybenzoin Hybrids as Antimicrobial Agents: Synthesis, In Vitro and In Silico Screening

Aitha

Thumma²,

Ambala

et al. 2023

ChemistrySelect

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show abstract

“…For the virulence assay, 10 7 cells in 200 µL of 1× phosphate-buffered saline of each isolate, including the reference SC5314 strain, were injected into the tail vein of six 4-weekold, non-pathogen-free BALB/c female mice to induce a systemic infection. A control group of 6 mice was injected with only 1× phosphate-buffered saline solution [1,13]. The mice were monitored for 30 days and the number of moribund mice was counted daily.…”

Section: Virulence Assaymentioning

confidence: 99%

“…Candida albicans is a ubiquitous polymorphic opportunistic eukaryotic fungal pathogen that can cause a range of infections, from mild cases of oral thrush to severe systemic candidiasis [1]. One of the most common causes of candidemia-fungal bloodstream infectionis C. albicans, the fourth most common pathogen found in hospitals, and the leading fungal pathogen [2].…”

Section: Introductionmentioning

confidence: 99%

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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“…Fluconazole, due to the presence of two triazoles in its structure and a phenyl ring containing two fluorine atoms in the meta position, interferes with sterol synthesis by inhibiting lanosterol 14α-demethylase, one of the critical enzymes of the cytochrome P450 system [ 8 ]. Therefore, fluconazole in therapy can lead to hepatotoxicity [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Synergic Effect of Phthalide Lactones and Fluconazole and Its New Analogues as a Factor Limiting the Use of Azole Drugs against Candidiasis

et al. 2022

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The resistance of Candida albicans and other pathogenic yeasts to azole antifungal drugs has increased rapidly in recent years and is a significant problem in clinical therapy. The current state of pharmacological knowledge precludes the withdrawal of azole drugs, as no other active substances have yet been developed that could effectively replace them. Therefore, one of the anti-yeast strategies may be therapies that can rely on the synergistic action of natural compounds and azoles, limiting the use of azole drugs against candidiasis. Synergy assays performed in vitro were used to assess drug interactions Fractional Inhibitory Concentration Index. The synergistic effect of fluconazole (1) and three synthetic lactones identical to those naturally occurring in celery plants—3-n-butylphthalide (2), 3-n-butylidenephthalide (3), 3-n-butyl-4,5,6,7-tetrahydrophthalide (4)—against Candida albicans ATCC 10231, C. albicans ATCC 2091, and C. guilliermondii KKP 3390 was compared with the performance of the individual compounds separately. MIC90 (the amount of fungistatic substance (in µg/mL) inhibiting yeast growth by 90%) was determined as 5.96–6.25 µg/mL for fluconazole (1) and 92–150 µg/mL for lactones 2–4. With the simultaneous administration of fluconazole (1) and one of the lactones 2–4, it was found that they act synergistically, and to achieve the same effect it is sufficient to use 0.58–6.73 µg/mL fluconazole (1) and 1.26–20.18 µg/mL of lactones 2–4. As fluconazole and phthalide lactones show synergy, 11 new fluconazole analogues with lower toxicity and lower inhibitory activity for CYP2C19, CYP1A2, and CYP2C9, were designed after in silico testing. The lipophilicity was also analyzed. A three-carbon alcohol with two rings was preserved. In all compounds 5–15, the 1,2,4-triazole rings were replaced with 1,2,3-triazole or tetrazole rings. The hydroxyl group was free or esterified with phenylacetic acid or thiophene-2-carboxylic acid chlorides or with adipic acid. In structures 11 and 12 the hydroxyl group was replaced with the fragment -CH2Cl or = CH2. Additionally, the difluorophenyl ring was replaced with unsubstituted phenyl. The structures of the obtained compounds were determined by 1H NMR, and 13C NMR spectroscopy. Molecular masses were established by GC-MS or elemental analysis. The MIC50 and MIC90 of all compounds 1–15 were determined against Candida albicans ATCC 10231, C. albicans ATCC 2091, AM 38/20, C. guilliermondii KKP 3390, and C. zeylanoides KKP 3528. The MIC50 values for the newly prepared compounds ranged from 38.45 to 260.81 µg/mL. The 90% inhibitory dose was at least twice as high. Large differences in the effect of fluconazole analogues 5–15 on individual strains were observed. A synergistic effect on three strains—Candida albicans ATCC 10231, C. albicans ATCC 2091, C. guilliermondii KKP 339—was observed. Fractional inhibitory concentrations FIC50 and FIC90 were tested for the most active lactone, 3-n-butylphthalide, and seven fluconazole analogues. The strongest synergistic effect was observed for the strain C. albicans ATCC 10231, FIC 0.04–0.48. The growth inhibitory amount of azole is from 25 to 55 µg/mL and from 3.13 to 25.3 µg/mL for 3-n-butylphthalide. Based on biological research, the influence of the structure on the fungistatic activity and the synergistic effect were determined.

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Molecular mechanism of fluconazole resistance and pathogenicity attributes of Lebanese Candida albicans hospital isolates

Cited by 11 publications

References 36 publications

Bis 1, 2, 3‐ Triazoles Linked Deoxybenzoin Hybrids as Antimicrobial Agents: Synthesis, In Vitro and In Silico Screening

Bis 1, 2, 3‐ Triazoles Linked Deoxybenzoin Hybrids as Antimicrobial Agents: Synthesis, In Vitro and In Silico Screening

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

Synergic Effect of Phthalide Lactones and Fluconazole and Its New Analogues as a Factor Limiting the Use of Azole Drugs against Candidiasis

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