Potential Basis for Amphotericin B Resistance in
            <i>Aspergillus terreus</i>

Blum, Gerhard; Perkhofer, Susanne; Haas, Hubertus; Schrettl, Markus; Würzner, Reinhard; Dierich, Manfred P.; Lass‐Flörl, Cornelia

doi:10.1128/aac.01280-07

Cited by 123 publications

(88 citation statements)

References 22 publications

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“…On the other hand, evidence suggests that A. fumigatus amphotericin B resistance is unlikely to emerge during treatment for invasive aspergillosis, as amphotericin B MICs remain similar between isolates recovered from patients before and those recovered (14). It was proposed that the basis for the amphotericin B resistance of A. terreus may be the high level of catalase production compared with that of A. fumigatus, although this remains unconfirmed (63).…”

Section: Aspergillus Fumigatus Drug Resistance: the Polyenesmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

499

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: Aspergillus Fumigatus Drug Resistance: the Polyenesmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

499

547

View full text Add to dashboard Cite

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“…Species-specific diagnosis of A. terreus opportunistic infections is clinically important due to this pathogen's resistance to the primary antifungal therapeutic amphotericin B (13,56,66). To date, the identification of A. terreus infections has challenged the most seasoned clinicians (29).…”

mentioning

confidence: 99%

Monoclonal Antibodies to Hyphal Exoantigens Derived from the Opportunistic Pathogen Aspergillus terreus

Nayak

Green

Janotka

et al. 2011

Clin. Vaccine Immunol.

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Aspergillus terreus has been difficult to identify in cases of aspergillosis, and clinical identification has been restricted to the broad identification of aspergillosis lesions in affected organs or the detection of fungal carbohydrates. As a result, there is a clinical need to identify species-specific biomarkers that can be used to detect invasive A. terreus disease. Monoclonal antibodies (MAbs) were developed to a partially purified preparation of cytolytic hyphal exoantigens (HEA) derived from A. terreus culture supernatant (CSN). Twentythree IgG1 isotype murine MAbs were developed and tested for cross-reactivity against hyphal extracts of 54 fungal species. Sixteen MAbs were shown to be specific for A. terreus. HEA were detected in conidia, hyphae, and in CSN of A. terreus. HEA were expressed in high levels in the hyphae during early stages of A. terreus growth at 37°C, whereas at room temperature the expression of HEA peaked by days 4 to 5. Expression kinetics of HEA in CSN showed a lag, with peak levels at later time points at room temperature and 37°C than in hyphal extracts. Serum spiking experiments demonstrated that human serum components do not inhibit detection of the HEA epitopes by MAb enzyme-linked immunosorbent assay (ELISA). Immunoprecipitation and proteomic analysis demonstrated that MAbs 13E11 and 12C4 immunoprecipitated a putative uncharacterized leucine aminopeptidase (Q0CAZ7), while MAb 19B2 recognized a putative dipeptidyl-peptidase V (DPP5). Studies using confocal laser scanning microscopy showed that the uncharacterized leucine aminopeptidase mostly localized to extracellular matrix structures while dipeptidyl-peptidase V was mostly confined to the cytoplasm.

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“…To our knowledge this is the first report of an AmB-resistant strain of A. flavus isolated directly from cave sediment. Resistance to AMB has already been documented for other Aspergillus species obtained from clinical samples (Blum et al, 2008;Van Der Linden et al, 2011;Hadrich et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Fungal AMB-resistance has been related with enzymatic activity against oxidative stress for some fungi (Laniado-Laborín & Cabrales-Vargas, 2009;Mesa-Arango et al, 2014). Blum et al (2008) showed that AMB-resistance in A. terreus was highly related with catalase production. Okamoto et al (2004) showed that oxidative damage induced by superoxide was the main activity of AMB against the yeast C. albicans.…”

Section: Discussionmentioning

confidence: 99%

Screening of antifungal susceptibility in cave-dwelling aspergilli and report of an amphotericin B-resistant Aspergillus flavus

Taylor¹,

Ferreira²,

Freitas³

et al. 2017

IJS

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Abstract:Caves are stable environments that favour the development of several microorganisms.The aspergilli represent a large number of species isolated from caves including strains capable of causing serious invasive opportunistic infections in humans. Considering that caves may harbour resistant strains to many antibiotics, investigation on the response of opportunistic aspergilli, isolated from pristine and tourist caves to antifungal agents and the mechanisms involved in resistance might be clinically relevant. A total of 32 strains of the species Aspergillus candidus, A. flavus, A. fumigatus, A. niger, A. tamarii, and A. terreus were isolated from caves in the iron quadrangle in Brazil. The strains were tested for their susceptibility to amphotericin B (AMB), itraconazole, voriconazole and terbinafine. One strain was analysed for the mechanism involved in the AMB-resistance, i.e., ergosterol content, lipid peroxidation and enzymatic activity of the antioxidant system. Terbinafine minimum inhibitory concentrations (MICs) ranged between 0.003 and 1.0 µg/mL; voriconazole MICs ranged between 2.0 and >16.0 µg/mL; itraconazole MICs ranged between 0.25 and 8.0 µg/mL and amphotericin B MICs ranged between 0.03 and 4.0 µg/mL. The AMB-resistant strain of A. flavus was detected with MIC value of 4 µg/mL. Resistance to AMB relied on higher ergosterol levels and increased enzymatic activity of the peroxidase and superoxidedismutase, with lower lipid peroxidation. These results enhance the knowledge of natural antifungal resistance in the subterranean ecosystem, and broaden the knowledge about the subterranean microbiota.Iron cave, Aspergillus flavus, antifungal drugs, amphotericin B, primary resistance

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Potential Basis for Amphotericin B Resistance in Aspergillus terreus

Cited by 123 publications

References 22 publications

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Monoclonal Antibodies to Hyphal Exoantigens Derived from the Opportunistic Pathogen Aspergillus terreus

Screening of antifungal susceptibility in cave-dwelling aspergilli and report of an amphotericin B-resistant Aspergillus flavus

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