Transcriptional Activation of Heat Shock Protein 90 Mediated Via a Proximal Promoter Region as Trigger of Caspofungin Resistance in Aspergillus fumigatus

Lamoth, Frédéric; Juvvadi, Praveen R.; Gehrke, Christopher; Asfaw, Yohannes G.; Steinbach, William J.

doi:10.1093/infdis/jit530

Cited by 59 publications

(79 citation statements)

References 38 publications

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“…Fungal Hsp90 promotes resistance to azole and echinocandin drugs, which has been well demonstrated in the pathogenic yeast Candida albicans (6,10,11). We have previously shown that genetic repression of A. fumigatus Hsp90 abolishes virulence in a murine model of IA (12). Compromising Hsp90-mediated stress responses by genetic modifications of the hsp90 promoter also potentiated the effect of caspofungin and abolished the paradoxical effect of this drug (7,12).…”

mentioning

confidence: 71%

“…Primers used in this study are listed in Table S1 in the supplemental material. Plasmids pUCGH (27) and pBluescript II SK(Ϫ) containing the hygromycin resistance cassette (12) were used for cloning (see Fig. S1 in the supplemental material).…”

Section: Methodsmentioning

confidence: 99%

“…We have previously shown that genetic repression of A. fumigatus Hsp90 abolishes virulence in a murine model of IA (12). Compromising Hsp90-mediated stress responses by genetic modifications of the hsp90 promoter also potentiated the effect of caspofungin and abolished the paradoxical effect of this drug (7,12). Because Hsp90 is a highly conserved protein in eukaryotes, identification of specific regions of the protein that are important for fungal virulence or antifungal resistance would be a critical step toward development of novel fungal-specific Hsp90 inhibitors.…”

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confidence: 99%

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Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus

Lamoth

Juvvadi

Soderblom

et al. 2014

Antimicrob Agents Chemother

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f Heat shock protein 90 (Hsp90) is an essential chaperone involved in the fungal stress response that can be harnessed as a novel antifungal target for the treatment of invasive aspergillosis. We previously showed that genetic repression of Hsp90 reduced Aspergillus fumigatus virulence and potentiated the effect of the echinocandin caspofungin. In this study, we sought to identify sites of posttranslational modifications (phosphorylation or acetylation) that are important for Hsp90 function in A. fumigatus. Phosphopeptide enrichment and tandem mass spectrometry revealed phosphorylation of three residues in Hsp90 (S49, S288, and T681), but their mutation did not compromise Hsp90 function. Acetylation of lysine residues of Hsp90 was recovered after treatment with deacetylase inhibitors, and acetylation-mimetic mutations (K27A and K271A) resulted in reduced virulence in a murine model of invasive aspergillosis, supporting their role in Hsp90 function. A single deletion of lysine K27 or an acetylationmimetic mutation (K27A) resulted in increased susceptibility to voriconazole and caspofungin. This effect was attenuated following a deacetylation-mimetic mutation (K27R), suggesting that this site is crucial and should be deacetylated for proper Hsp90 function in antifungal resistance pathways. In contrast to previous reports in Candida albicans, the lysine deacetylase inhibitor trichostatin A (TSA) was active alone against A. fumigatus and potentiated the effect of caspofungin against both the wild type and an echinocandin-resistant strain. Our results indicate that the Hsp90 K27 residue is required for azole and echinocandin resistance in A. fumigatus and that deacetylase inhibition may represent an adjunctive anti-Aspergillus strategy. Invasive aspergillosis (IA) is a life-threatening infection in the increasing population of patients with depressed immune systems, such as cancer patients or transplant recipients (1). Three antifungal drug classes are approved for the treatment of IA: the triazoles (e.g., voriconazole), the polyenes (e.g., amphotericin B), and the echinocandins (e.g., caspofungin), all of them targeting the fungal cell membrane or cell wall (2). The emergence in Aspergillus fumigatus of resistance to triazoles, the preferred primary therapy against IA, is a growing concern (3). Moreover, the toxicity of polyenes often limits their use, and the echinocandins possess only fungistatic activity against Aspergillus spp. Combination antifungal therapy with existing classes of agents has shown limited promise (4), suggesting the need for new therapeutic options.One novel therapeutic approach consists of the development of drugs targeting intracellular signaling proteins involved in compensatory mechanisms of the cell wall. The heat shock protein 90 (Hsp90)-calcineurin axis is a crucial element governing stress adaptation processes in fungi (5). Calcineurin inhibitors (FK506 and cyclosporine) and Hsp90 inhibitors (geldanamycin,, and 17-demethylaminoethylamino-17-demethoxygeldanamycin [17-DMAG]) are active a...

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confidence: 71%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus

Lamoth

Juvvadi

Soderblom

et al. 2014

Antimicrob Agents Chemother

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“…Genetic or pharmacological compromise of Hsp90 function reduces basal echinocandin tolerance and resistance of C. albicans, C. glabrata, and A. fumigatus (Cowen and Lindquist 2005;Cowen 2009;Cowen et al 2009;Singh et al 2009;Singh-Babak et al 2012;Lamoth et al 2014a). Inhibition of Hsp90 reduces echinocandin resistance acquired by mutation in the drug target, and resistance that evolved in the human host Singh-Babak et al 2012).…”

Section: Hsp90mentioning

confidence: 99%

Mechanisms of Antifungal Drug Resistance

Cowen

Sanglard

Howard

et al. 2014

Cold Spring Harb Perspect Med

493

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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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“…112 Recent work in A. fumigatus has shown that Hsp90 is required for the caspofungin mediated paradoxical growth response, and that disrupting Hsp90 circuitry potentiates the antifungal activity of caspofungin. 113 Furthermore, targeting the Hsp90-calcineurin pathway through the combination of respective inhibitors not only resulted in fungicidal activity against azole-resistant A. fumigatus strains but also showed distinct patterns of susceptibility among different fungal species revealing this to be a promising alternative strategy. 17,91 Calcineurin: An attractive antifungal target Due to limited drug efficacy and emerging resistance to drugs, current antifungal classes would benefit from adjunctive agents focused on separate cellular pathways that can be used in combination therapy.…”

Section: Heat Shock Protein 90 and Calcineurin Inhibitors: Another Prmentioning

confidence: 99%

Calcineurin in fungal virulence and drug resistance: Prospects for harnessing targeted inhibition of calcineurin for an antifungal therapeutic approach

et al. 2016

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Increases in the incidence and mortality due to the major invasive fungal infections such as aspergillosis, candidiasis and cryptococcosis caused by the species of Aspergillus, Candida and Cryptococcus, are a growing threat to the immunosuppressed patient population. In addition to the limited armamentarium of the current classes of antifungal agents available (pyrimidine analogs, polyenes, azoles, and echinocandins), their toxicity, efficacy and the emergence of resistance are major bottlenecks limiting successful patient outcomes. Although these drugs target distinct fungal pathways, there is an urgent need to develop new antifungals that are more efficacious, fungalspecific, with reduced or no toxicity and simultaneously do not induce resistance. Here we review several lines of evidence which indicate that the calcineurin signaling pathway, a target of the immunosuppressive drugs FK506 and cyclosporine A, orchestrates growth, virulence and drug resistance in a variety of fungal pathogens and can be exploited for novel antifungal drug development.

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Transcriptional Activation of Heat Shock Protein 90 Mediated Via a Proximal Promoter Region as Trigger of Caspofungin Resistance in Aspergillus fumigatus

Cited by 59 publications

References 38 publications

Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus

Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus

Mechanisms of Antifungal Drug Resistance

Calcineurin in fungal virulence and drug resistance: Prospects for harnessing targeted inhibition of calcineurin for an antifungal therapeutic approach

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