Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the presence of itraconazole in an itraconazole resistant clinical isolate

Slaven, J.; Anderson, Michael J.; Sanglard, Dominique; Dixon, Graham K.; Billé, Jacques; Roberts, Ian S.; Denning, David W.

doi:10.1016/s1087-1845(02)00016-6

Cited by 178 publications

(133 citation statements)

References 43 publications

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“…An analysis of atrF mRNA from susceptible isolates and from the earliest-identified itraconazole-resistant isolates revealed that resistance correlated with increased levels of atrF (539). The MDR pumps are also involved in A. fumigatus azole resistance.…”

Section: Upregulation Of Drug Pumpsmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

489

547

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SUMMARY Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans , several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus , which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans , C. neoformans , and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

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Section: Upregulation Of Drug Pumpsmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

489

547

View full text Add to dashboard Cite

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“…As a potential methodological limitation, it could be argued that this platform does not detect triazole resistance unassociated with cyp51A gene alterations (e.g., drug pumps), and it does not detect new triazole resistance mutations that might be present in the A. fumigatus cyp51A gene. However, such mechanisms have rarely been described in clinical isolates, although they have been reported in laboratory mutants (33,40). Nevertheless, the dynamic platform can accommodate new resistance mutations as they arise.…”

Section: Discussionmentioning

confidence: 99%

Rapid Detection of Triazole Antifungal Resistance in Aspergillus fumigatus

et al. 2008

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Triazole resistance in Aspergillus fumigatus is an uncommon but rising phenomenon. Susceptibility testing is rarely performed and can take 48 h or longer, which is an impediment to effective therapy. Molecular diagnostic probing of well-defined resistance mechanisms, which serve as surrogate markers, provides an alternative approach to rapidly (within hours) and efficiently identify resistant strains. The mechanisms of triazole resistance in A. fumigatus are limited to amino acid substitutions in the drug target Cyp51A and include amino acid substitutions at the positions Gly 54, Gly 138, Met 220, and Leu 98, coupled with a tandem repetition in the gene promoter. We report the development of a real-time PCR assay utilizing molecular beacons to assess triazole resistance markers in A. fumigatus. When combined in a multiplex platform, the assay provides a comprehensive evaluation of drug resistance in A. fumigatus.

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“…In A. fumigatus, decreased intracellular accumulation of itraconazole has been observed in itraconazole-resistant clinical isolates and laboratory-derived strains (Denning et al 1997;Manavathu et al 1999). Whereas the impact of specific transporters on azole resistance of A. fumigatus remains largely enigmatic, ABC transporter genes are up-regulated in response to azole exposure (AfuMDR1, AfuMDR2, and five genes designated abcA-E) (Tobin et al 1997;da Silva Ferreira et al 2006), and in resistant clinical isolates (Slaven et al 2002;Nascimento et al 2003). AfuMDR1, renamed CDR1B, encodes the only transporter implicated directly in A. fumigatus azole resistance (Fraczek et al 2013).…”

Section: Drug Effluxmentioning

confidence: 99%

Mechanisms of Antifungal Drug Resistance

Cowen

Sanglard

Howard

et al. 2014

Cold Spring Harb Perspect Med

Self Cite

471

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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Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the presence of itraconazole in an itraconazole resistant clinical isolate

Cited by 178 publications

References 43 publications

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Rapid Detection of Triazole Antifungal Resistance in Aspergillus fumigatus

Mechanisms of Antifungal Drug Resistance

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