Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species

Czajka, Karolina M.; Venkataraman, Krishnan; Brabant-Kirwan, Danielle; Santi, Stacey A.; Verschoor, Chris; Appanna, Vasu D.; Singh, Ravi; Saunders, Deborah P.; Tharmalingam, Sujeenthar

doi:10.3390/cells12222655

Cited by 14 publications

(8 citation statements)

References 244 publications

(390 reference statements)

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“…Echinocandin resistance, particularly when combined with resistance to azole and amphotericin B (pan-resistance), is a significant clinical and public health concern [42,89]. Antifungal drug resistance in C. auris is acquired through various mechanisms, including the alteration of drug targets, increased efflux pump activity, or the activation of cellular stress response pathways [90]. These mechanisms are not unique to C. auris [91].…”

Section: Antifungal Drug Resistance In C Aurismentioning

confidence: 99%

Candida auris Outbreaks: Current Status and Future Perspectives

De Gaetano,

Midiri,

Mancuso

et al. 2024

Microorganisms

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Candida auris has been identified by the World Health Organization (WHO) as a critical priority pathogen on its latest list of fungi. C. auris infections are reported in the bloodstream and less commonly in the cerebrospinal fluid and abdomen, with mortality rates that range between 30% and 72%. However, no large-scale epidemiology studies have been reported until now. The diagnosis of C. auris infections can be challenging, particularly when employing conventional techniques. This can impede the early detection of outbreaks and the implementation of appropriate control measures. The yeast can easily spread between patients and in healthcare settings through contaminated environments or equipment, where it can survive for extended periods. Therefore, it would be desirable to screen patients for C. auris colonisation. This would allow facilities to identify patients with the disease and take appropriate prevention and control measures. It is frequently unsusceptible to drugs, with varying patterns of resistance observed among clades and geographical regions. This review provides updates on C. auris, including epidemiology, clinical characteristics, genomic analysis, evolution, colonisation, infection, identification, resistance profiles, therapeutic options, prevention, and control.

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Section: Antifungal Drug Resistance In C Aurismentioning

confidence: 99%

Candida auris Outbreaks: Current Status and Future Perspectives

De Gaetano,

Midiri,

Mancuso

et al. 2024

Microorganisms

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“…However, administration of these drugs has limitations, as they are contraindicated in pregnancy and are associated with vaginal and gastrointestinal adverse effects that can reduce compliance with treatment. The emerging resistance of Candida to azoles is another factor that can trigger therapeutic failure and prompt a search for new treatment options [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

The Efficacy of Hybrid Vaginal Ovules for Co-Delivery of Curcumin and Miconazole against Candida albicans

Bezerra,

y Araújo,

Alves-Júnior

et al. 2024

Pharmaceutics

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Curcumin (CUR) is a natural compound that can be combined with miconazole (MCZ) to improve vulvovaginal candidiasis (VVC) caused by Candida albicans treatment’s efficacy. This study aimed to develop ureasil–polyether (U-PEO) vaginal ovules loaded with CUR and MCZ for the treatment of VVC. Physicochemical characterization was performed by thermogravimetry (TGA), differential thermal analysis (DTA), Fourier transform infrared spectroscopy (FTIR), and in vitro release. Antifungal assays were used to determine minimum inhibitory concentrations (MICs) and synergism between CUR and MCZ, and the activity of U-PEO ovules were performed by microdilution and agar diffusion. TGA results showed high thermal stability of the hybrid ovules. In DTA, the amorphous character of U-PEO and a possible interaction between CUR and MCZ were observed. FTIR showed no chemical incompatibility between the drugs. In vitro release resulted in 80% of CUR and 95% of MCZ released within 144 h. The MICs of CUR and MCZ were 256 and 2.5 µg/mL, respectively. After combining the drugs, the MIC of MCZ decreased four-fold to 0.625 µg/mL, while that of CUR decreased eight-fold to 32 µg/mL. Synergism was confirmed by the fractional inhibitory concentration index (FICI) equal to 0.375. U-PEO alone showed no antifungal activity. U-PEO/MCZ and U-PEO/CUR/MCZ ovules showed the greatest zones of inhibition (≥18 mm). The results highlight the potential of the ovules to be administered at a lower frequency and at reduced doses compared to available formulations.

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“…For example, chromosome 3 possesses CDR1 and CDR2 , and chromosome 6 carries MDR1 , and an increase in the copy number of these chromosomes leads to the overexpression of respective transporters and azole resistance [ 19 ]. Polyenes like amphotericin B (Amp B) and nystatin bind to ergosterol and depolarize the membrane to cause cell death [ 6 , 20 ]. Although polyene resistance in clinical isolates is relatively less explored, few reports link it to ERG3 and ERG6 functions in C. albicans and C. glabrata [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains of Candida albicans

Utkalaja,

Sahu,

Parida

et al. 2024

JoF

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The incidence of infections caused by Candida species, specifically by drug-resistant isolates, is a major health concern as they can disseminate to and colonize most vital organs, enhancing morbidity and mortality. Several molecular mechanisms have been reported to be involved in drug resistance. These are mostly drug- and isolate-specific. Here, we characterized three different genetically modified strains of C. albicans that were multi-drug-resistant (MDR) and deciphered a uniform mechanism responsible for resistance. DNA polymerase epsilon (Polε) is a leading strand-specific polymerase consisting of four subunits, namely, Pol2, Dpb2, Dpb3, and Dpb4. The deletion of one or both of the Dpb3 and Dpb4 subunits in C. albicans rendered multi-drug resistance. A detailed characterization of these strains revealed that acquired mutagenesis, drug efflux pumps, and other known mechanisms did not play a significant role because the complemented strain showed drug sensitivity. More importantly, the function of heat shock protein 90 (Hsp90) in these knockout strains is critical for reducing susceptibility to several antifungal drugs. Cell wall deformity and composition in these strains can add to such a phenotype. The inhibition of Hsp90 function by geldanamycin and tricostatin A sensitized the MDR strains to antifungals. Considering our earlier research and this report, we suggest that replication stress induces Hsp90 expression and activity in order to orchestrate a cellular stress response circuit and thus develop fungal drug resistance. Thus, Hsp90 is an important drug target for use in combinatorial therapy.

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Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species

Cited by 14 publications

References 244 publications

Candida auris Outbreaks: Current Status and Future Perspectives

Candida auris Outbreaks: Current Status and Future Perspectives

The Efficacy of Hybrid Vaginal Ovules for Co-Delivery of Curcumin and Miconazole against Candida albicans

Hsp90-Mediated Multi-Drug Resistance in DNA Polymerase-Defective Strains of Candida albicans

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