Within the limited antifungal armamentarium, the azole antifungals are the most frequent class used to treat Candida infections. Azole antifungals such as fluconazole are often preferred treatment for many Candida infections as they are inexpensive, exhibit limited toxicity, and are available for oral administration. There is, however, extensive documentation of intrinsic and developed resistance to azole antifungals among several Candida species. As the frequency of azole resistant Candida isolates in the clinical setting increases, it is essential to elucidate the mechanisms of such resistance in order to both preserve and improve upon the azole class of antifungals for the treatment of Candida infections. This review examines azole resistance in infections caused by C. albicans as well as the emerging non-albicans Candida species C. parapsilosis, C. tropicalis, C. krusei, and C. glabrata and in particular, describes the current understanding of molecular basis of azole resistance in these fungal species.

/pdf/azole-antifungal-resistance-in-candida-albicans-and-emerging-131otr2ik9.pdf

Azole antifungal resistance in Candida albicans and emerging non-albicans Candida Species

Introduction: Clinicians are increasingly challenged by patients with refractory vulvovaginal candidiasis (VVC) caused by azole-resistant Candida species. Fluconazole resistant C.albicans is a grow...

Current treatment options for vulvovaginal candidiasis caused by azole-resistant Candida species.

The emergence of new fungal pathogens makes the development of new antifungal drugs a medical imperative that in recent years motivates the talents of numerous investigators across the world. Understanding not only the structural families of these drugs but also their biological targets provides a rational means for evaluating the merits and selectivity of new agents for fungal pathogens and normal cells. An equally important aspect of modern antifungal drug development takes a balanced look at the problems of drug potency and drug resistance. The future development of new antifungal agents will rest with those who employ synthetic and semisynthetic methodology as well as natural product isolation to tackle these problems and with those who possess a clear understanding of fungal cell architecture and drug resistance mechanisms. This review endeavors to provide an introduction to a growing and increasingly important literature, including coverage of the new developments in medicinal chemistry since 2015, and also endeavors to spark the curiosity of investigators who might enter this fascinatingly complex fungal landscape.

A comprehensive overview of the medicinal chemistry of antifungal drugs: perspectives and promise.

Candida albicans is an opportunistic yeast and the major human fungal pathogen in the USA, as well as in many other regions of the world. Infections with C. albicans can range from superficial mucosal and dermatological infections to life-threatening infections of the bloodstream and vital organs. The azole antifungals remain an important mainstay treatment of candidiasis and therefore the investigation and understanding of the evolution, frequency and mechanisms of azole resistance are vital to improving treatment strategies against this organism. Here the organism C. albicans and the genetic changes and molecular bases underlying the currently known resistance mechanisms to the azole antifungal class are reviewed, including up-regulated expression of efflux pumps, changes in the expression and amino acid composition of the azole target Erg11 and alterations to the organism’s typical sterol biosynthesis pathways. Additionally, we update what is known about activating mutations in the zinc cluster transcription factor (ZCF) genes regulating many of these resistance mechanisms and review azole import as a potential contributor to azole resistance. Lastly, investigations of azole tolerance in C. albicans and its implicated clinical significance are reviewed.

Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus Candida albicans.

Synthesis, antifungal activity of caffeic acid derivative esters, and their synergism with fluconazole and nystatin against Candida spp.

Fluconazole susceptibility of 3,056 clinical isolates of Candida species from 2005 to 2009 in a tertiary-care hospital

To obtain the operation characteristics of the hybrid excitation permanent magnet synchronous generator (HEPMSG) utilizing tooth harmonic for excitation quickly, it is important to calculate the parameter. Based on the air-gap permeance method, this paper derives the inductance parameter considering the slots of stator and rotor. And the amplitude and phase angle of the inductance parameter are calculated using finite element method(FEM). According to the inductance parameter and circuit equation, the armature winding voltage and current, and the field current are obtained. The tested results verify the correctness of the parameter calculation.

Parameter calculation of the hybrid excitation synchronous machine system utilizing tooth harmonic for excitation

Fluconazole resistance of Candida albicans has been reported to be the result of one or more specific point mutations in ERG11 gene. In this study, we amplified and sequenced the entire ERG11 coding sequence of 72 isolates of C. albicans to search for possible mutations. Twenty-seven silent mutations and 14 missense mutations were identified. While the mutations K342R and V437I were found as single-amino-acid changes in Erg11p, other mutations were detected simultaneously in individual isolates. Several different clinical isolates had the same pattern of multiple amino acid alternations: (1) A114S with Y257H was identified in 11 resistant and 3 susceptible dose-dependent isolates without any other silent mutation and may be associated with resistance; (2) Y132H combined with G450E was identified in two fluconazole-resistant isolates and is known to contribute to resistance; and (3) the coexistence of D116E, K128T, Y132H, and G465S was first described in five reduced-susceptibility isolates, but the correlation of this pattern with resistance is still uncertain. These data indicate that multiple amino acid substitutions in Erg11p were found frequently in clinical isolates and may be associated with fluconazole resistance.

In vitro fluconazole susceptibility of 1,903 clinical isolates of Candida albicans and the identification of ERG11 mutations.

The increasing incidence of vulvovaginal candidiasis (VVC) and the emergence of fluconazole resistance are an indisputable fact. However, little information is available regarding the correlation between fluconazole resistance in vaginal Candida albicans and the expression of drug efflux pump genes. In this study, we investigated the species distribution, fluconazole susceptibility profiles and the mechanisms of fluconazole resistance in Candida strains. In total, 785 clinical Candida isolates were collected from patients with VVC. C. albicans was the most frequently isolated species(n = 529) followed by C. glabrata (n = 164) and C. krusei (n = 57). Of all Candida isolates, 4.7% were resistant to fluconazole. We randomly selected 18 fluconazole resistant isolates of C. albicans to evaluate the expression of CDR1, CDR2, MDR1 and FLU1 genes. Compared with fluconazole-susceptible C. albicans isolates, CDR1 gene expression displayed 3.16-fold relative increase, which was statistically significant. CDR2, MDR1 and FLU1 overexpression was observed in several fluconazole-resistant C. albicans isolates, but statistical significance was not achieved. These results demonstrate a high frequency of non-albicans species (32.6%); however, C. albicans is the most common Candida species implicated in vaginitis, and this strain displays considerable fluconazole resistance. Meanwhile, our study further indicates that fluconazole resistance in C. albicans may correlate with CDR1 gene overexpression.

Vulvovaginal candidiasis: species distribution, fluconazole resistance and drug efflux pump gene overexpression.

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Fluconazole susceptibility of 3,056 clinical isolates of Candida species from 2005 to 2009 in a tertiary-care hospital

Parameter calculation of the hybrid excitation synchronous machine system utilizing tooth harmonic for excitation

In vitro fluconazole susceptibility of 1,903 clinical isolates of Candida albicans and the identification of ERG11 mutations.

Vulvovaginal candidiasis: species distribution, fluconazole resistance and drug efflux pump gene overexpression.