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Emerging Resistance Among Candida Species: Trends and Treatment Considerations for Candidemia
Published in Robert C. Owens, Lautenbach Ebbing, Antimicrobial Resistance, 2007
Fluconazole, which was first introduced in 1990, has the following mechanism of action. It inhibits the fungal cytochrome P-450 dependent enzyme, 14-α-demethylase, which converts lanosterol to ergosterol, an important component of fungal cell membranes. A decrease in ergosterol synthesis coupled with an accumulation of intermediary byproducts results in fungal cell membrane disruption and death. Hypothetically, fluconazole resistance in C. glabrata could be due to several different mechanisms. Point mutations could occur in the ERG11 gene, which encodes 14-α-demethylase, thereby altering its binding to fluconazole. Prior fluconazole use could also upregulate the expression of the ERG11 gene, resulting in more 14-α-demethylase compared to the available fluconazole. Lastly, resistance could occur via efflux pumps. Of these possible resistance mechanisms, PCR studies have suggested that the upregulation of efflux pumps, specifically those of the ATP-binding cassette transporter family, plays an integral role (15,16).
Antifungal drug resistance: Significance and mechanisms
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Sharvari Dharmaiah, Rania A. Sherif, Pranab K. Mukherjee
A major mechanism of azole resistance is induction or overexpression of drug efflux pumps (Candida drug resistance, CDR) and transporters (major facilitator superfamily, MFS), which mediate clearance of the drug from fungal cells [165–170]. Different studies have demonstrated that multiple mechanisms can be operative in fungal cells and contribute to azole resistance in C. albicans [171–173]. White et al. [171] evaluated mRNA levels in a series of 17 clinical isolates taken from a single HIV-infected patient over 2 years, during which time the levels of fluconazole resistance of the strain increased over 200-fold. These investigators reported increased mRNA levels of ERG16 (which encodes the 14α-demethylase enzyme), CDR1, and MDR1 in this series, which correlated with increases in fluconazole resistance of the isolates. In a second study, Franz et al. [172] reported the isolation of five C. albicans isolates from two AIDS patients with oropharyngeal candidiasis, from recurrent episodes of infection, which became gradually resistant against fluconazole during treatment. Isolates from patient 1 exhibited enhanced expression of MDR1 and constitutively high expression of ERG11, which correlated with a stepwise development of fluconazole resistance. In the isolates from patient 2, increased MDR1 mRNA levels and the change from heterozygosity to homozygosity for a mutant form of the ERG11 gene correlated with continuously decreased drug susceptibility, reduced drug accumulation and increased resistance in activity of sterol 14alpha-demethylase. Exposure of cells to fluconazole can also induce expression of CDR1, which can contribute to development of azole resistance [174].
Itraconazole
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Jeniel E. Nett, David R. Andes
Itraconazole resistance has been reported for a variety of Candida spp., but is most common for C. glabrata, where 39% of isolates are resistant to itraconazole (Pfaller et al., 2011) (Table 154.2). The predominant drug resistance mechanisms that have been shown to be responsible for azole resistance in C. albicans include increased expression of the CDR1 and CDR2 ATP-dependent efflux pumps and point mutations in ERG11, the gene encoding the azole target, 14-alpha-demethylase (White et al., 2002). For C. glabrata, the main mechanism of resistance involves upregulation of the ATP-dependent efflux pump CDR1 (Sanglard et al., 1999). Cross-resistance among the azoles has been demonstrated for most Candida spp., including C. glabrata, C. albicans, C. tropicalis, and C. parapsilosis (Sabatelli et al., 2006). A study of 157 fluconazole-resistant (MIC > 64 µg/ml) Candida isolates found that 71% were also resistant to itraconazole (MIC ≥ 1 µg/ml) (Pfaller et al., 2003). A similar study examined the resistance profiles of 123 colonizing yeast isolates from neutropenic patients with hematologic malignancies and identified cross-resistance between fluconazole and itraconazole for 14 strains (Chryssanthou et al., 2004). Azole cross-resistance has been described for most Candida spp., but less commonly with C. krusei. In fluconazole-resistant strains (MIC > 32 µg/ml), cross-resistance to itraconazole (MIC > 4 µg/ml) was also observed in 18% of C. albicans isolates, 61% of C. glabrata isolates, and 56% of C. tropicalis isolates, but only 13% of C. krusei isolates (Johnson et al., 1995).
In vitro and in vivo anti-Candida activity of citral in combination with fluconazole
Published in Journal of Oral Microbiology, 2022
Katherine Miranda-Cadena, Cristina Marcos-Arias, Aitzol Perez-Rodriguez, Iván Cabello-Beitia, Estibaliz Mateo, Elena Sevillano, Lucila Madariaga, Guillermo Quindós, Elena Eraso
With regard to the involvement of citral in the expression of the ERG11 gene, our findings were not conclusive. The relative changes in expression were not significant in any case, despite the fact that a slight ERG11 upregulation was observed. This could be due to the low concentrations of fluconazole used in this study [47]. However, in a previous study using carvacrol, down-regulated expression of ERG3 and ERG11 was described at different concentrations (IC, 25 mg/L, and 0.5× IC) [48]. Although ERG11 encodes an essential enzyme in the C. albicans pathway and the Hot-spot mutations and its overexpression are associated with fluconazole resistance, there are about 20 genes involved in the ergosterol biosynthesis, which have not been included in this study. Hence, if citral interferes with the ergosterol pathway, it should be independent to ERG11 or likely dose dependent, and other ERG genes should be considered. In addition, it is relevant to note that antifungal resistance is often the result of the sum of several mechanisms, and further study would be necessary for a better understanding.
Drug design strategies for the treatment azole-resistant candidiasis
Published in Expert Opinion on Drug Discovery, 2022
Setareh Moghimi, Mohammad Shafiei, Alireza Foroumadi
If the drug entered and reached the target protein, the second class of fungal cell resistance, the reduction of the drug affinity to the target is considered working through altering or overexpressing the protein. To date, an amino acid substitution in Erg11 has been implicated in many fluconazole-resistant clinical isolates. Genome sequencing of resistant C. albicans isolates revealed that numerous mutations in the fungus-specific external loop, the catalytic site, and the proximal surface of the lanosterol demethylase enzyme are conferring to lower drug-binding affinity. Of note, among these amino acid substitutions, three of them (e.g. Y132F, K143R, and F126L) have been confirmed with elevated MIC values compared to azole drugs like fluconazole and voriconazole [27]. Evidence suggested that elevated levels of ERG11 mRNA transcription in azole-resistant Candida strains induce the overexpression of lanosterol 14α-demethylase enzyme. As a result of long-term exposure to azoles, the expression of ERG11 is regulated by a transcriptional activator, namely UPC2, by which some gain-of-function mutations led to the promoted strong constitutive ERG11 expression [28–30]. This overexpression mainly occurrs among clinical isolates of azole-resistant C. albicans. Also, the importance of the UPC2 transcription factor in regulating C. albicans azole resistance was demonstrated by an in-vitro experimental study exhibiting the disruption of the transcriptional activator in an azole-resistant clinical isolate, abrogated ERG11 overexpression, reduced cellular ergosterol level, and enhanced azole susceptibility.
Current treatment options for vulvovaginal candidiasis caused by azole-resistant Candida species
Published in Expert Opinion on Pharmacotherapy, 2018
Azoles are fungistatic against Candida and act by binding to and inhibiting the intracellular target enzymes involved in biosynthesis of ergosterol. Fluconazole resistance in C. albicans can occur through different mechanisms including gene mutations in ERG11, critical to the function of the azole drug target enzyme 14 alpha-demethylase, crucial in the synthesis of ergosterol, a major component of Candida cell membrane. Resistance results from increased expression of the ERG11 gene. Also involved in drug resistance are other alterations in cell membrane sterol biosynthesis [21–27].