Mechanisms of azole resistance in 52 clinical isolates of Candida tropicalis in China

Jiang, Cen; Dong, Danfeng; Yu, Bo; Cai, Gang; Wang, Xuefeng; Ji, Yuhua; Peng, Yibing

doi:10.1093/jac/dks481

Cited by 134 publications

(156 citation statements)

References 31 publications

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“…This phenomenon could be explained by higher membrane permeability due to changes in the sterol composition of the membrane. However, analysis of the uptake and efflux of R6G for all azole-resistant or wild-type C. tropicalis strains shows that the efflux pumps do not seem to play a fundamental role in azole resistance in C. tropicalis, in agreement with previous results (14,27).…”

Section: Discussionsupporting

confidence: 90%

“…However, antifungals have been used extensively for the prophylaxis or treatment of candidiasis, and there are increasing reports of azole resistance for this species (13,14,27,54). In fact, the azole-resistant clinical isolates of C. tropicalis studied in this work were recovered from two patients suffering from candidemia and treated with different antifungals (Table 1).…”

Section: Discussionmentioning

confidence: 97%

“…In addition, increasing evidence points to a relationship between amino acid substitutions and changes in protein conformation involved in azole resistance (25,26). For C. tropicalis, overexpression of C. tropicalis ERG11 (CtERG11) associated with missense mutations (Y132F or S154F) has been described as the azole resistance mechanism in clinical isolates (14,27). Additionally, in vitro develop-ment of fluconazole resistance in C. tropicalis linked to the upregulation of two multidrug efflux transporter genes, CtMDR1 and CtCDR1, has been reported (28).…”

mentioning

confidence: 99%

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Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

Forastiero

Mesa-Arango

Alastruey‐Izquierdo

et al. 2013

Antimicrob Agents Chemother

100

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

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Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

Forastiero

Mesa-Arango

Alastruey‐Izquierdo

et al. 2013

Antimicrob Agents Chemother

100

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“…Overexpression of ERG11 has also been reported for azole-resistant isolates of C. glabrata, Candida parapsilosis, Candida tropicalis, and Candida krusei (Barchiesi et al 2000;Redding et al 2002;Vandeputte et al 2005;Rogers et al 2006;Jiang et al 2013). The mechanism for this overexpression or its contribution to azole resistance in these species remains largely unknown.…”

Section: Alterations In Ergosterol Biosynthetic Enzymesmentioning

confidence: 99%

Mechanisms of Antifungal Drug Resistance

Cowen

Sanglard

Howard

et al. 2014

Cold Spring Harb Perspect Med

478

399

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Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug-resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance.

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“…Antifungal drug-resistant C. tropicalis isolates are frequently isolated from patients with candidemia or leukemia and can pose treatment challenges (10,12,15,42,43). Calcineurin is a potential drug target on the basis of its requirement for drug tolerance and virulence in multiple fungal pathogens (24,(44)(45)(46).…”

Section: Identification Of Calcineurin and Crz1 Orthologs In C Tropimentioning

confidence: 99%

Calcineurin Controls Hyphal Growth, Virulence, and Drug Tolerance of Candida tropicalis

Chen

Huang

et al. 2014

Eukaryot Cell

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f Candida tropicalis, a species closely related to Candida albicans, is an emerging fungal pathogen associated with high mortality rates of 40 to 70%. Like C. albicans and Candida dubliniensis, C. tropicalis is able to form germ tubes, pseudohyphae, and hyphae, but the genes involved in hyphal growth machinery and virulence remain unclear in C. tropicalis. Recently, echinocandinand azole-resistant C. tropicalis isolates have frequently been isolated from various patients around the world, making treatment difficult. However, studies of the C. tropicalis genes involved in drug tolerance are limited. Here, we investigated the roles of calcineurin and its potential target, Crz1, for core stress responses and pathogenesis in C. tropicalis. We demonstrate that calcineurin and Crz1 are required for hyphal growth, micafungin tolerance, and virulence in a murine systemic infection model, while calcineurin but not Crz1 is essential for tolerance of azoles, caspofungin, anidulafungin, and cell wall-perturbing agents, suggesting that calcineurin has both Crz1-dependent and -independent functions in C. tropicalis. In addition, we found that calcineurin and Crz1 have opposite roles in controlling calcium tolerance. Calcineurin serves as a negative regulator, while Crz1 plays a positive role for calcium tolerance in C. tropicalis.

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Mechanisms of azole resistance in 52 clinical isolates of Candida tropicalis in China

Abstract: The up-regulation and mutations of ERG11 mediate azole resistance of C. tropicalis.

Cited by 134 publications

References 31 publications

Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

Candida tropicalis Antifungal Cross-Resistance Is Related to Different Azole Target (Erg11p) Modifications

Mechanisms of Antifungal Drug Resistance

Calcineurin Controls Hyphal Growth, Virulence, and Drug Tolerance of Candida tropicalis

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