Treatment of drug-resistant<i>Aspergillus</i>infection

Aigner, Maria; Lass‐Flörl, Cornelia

doi:10.1517/14656566.2015.1083976

Cited by 21 publications

(20 citation statements)

References 15 publications

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“…Amphotericin B, for a long time the first choice for the treatment of systemic aspergillosis, is frequently replaced with azole derivatives mainly because of its severe side effects. Increasing resistance to azoles, however, reduces their success and requires alternative therapies (47). Ideally, novel drugs will specifically target important enzymes or virulence factors of fungi without affecting their host.…”

Section: Discussionmentioning

confidence: 99%

A Class 1 Histone Deacetylase with Potential as an Antifungal Target

Bauer

Varadarajan

Pidroni

et al. 2016

mBio

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Histone deacetylases (HDACs) remove acetyl moieties from lysine residues at histone tails and nuclear regulatory proteins and thus significantly impact chromatin remodeling and transcriptional regulation in eukaryotes. In recent years, HDACs of filamentous fungi were found to be decisive regulators of genes involved in pathogenicity and the production of important fungal metabolites such as antibiotics and toxins. Here we present proof that one of these enzymes, the class 1 type HDAC RpdA, is of vital importance for the opportunistic human pathogen Aspergillus fumigatus. Recombinant expression of inactivated RpdA shows that loss of catalytic activity is responsible for the lethal phenotype of Aspergillus RpdA null mutants. Furthermore, we demonstrate that a fungus-specific C-terminal region of only a few acidic amino acids is required for both the nuclear localization and catalytic activity of the enzyme in the model organism Aspergillus nidulans. Since strains with single or multiple deletions of other classical HDACs revealed no or only moderate growth deficiencies, it is highly probable that the significant delay of germination and the growth defects observed in strains growing under the HDAC inhibitor trichostatin A are caused primarily by inhibition of catalytic RpdA activity. Indeed, even at low nanomolar concentrations of the inhibitor, the catalytic activity of purified RpdA is considerably diminished. Considering these results, RpdA with its fungus-specific motif represents a promising target for novel HDAC inhibitors that, in addition to their increasing impact as anticancer drugs, might gain in importance as antifungals against life-threatening invasive infections, apart from or in combination with classical antifungal therapy regimes.

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Section: Discussionmentioning

confidence: 99%

A Class 1 Histone Deacetylase with Potential as an Antifungal Target

Bauer

Varadarajan

Pidroni

et al. 2016

mBio

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“…Because mammalian cells do not have a cell wall, their target allows for significantly less toxicity and drug-drug interactions as compared to other antifungals [32,33]. These drugs were originally approved for treatment of aspergillosis infections that were refractory to treatment with other antifungals [30,34,35], but they have since been approved for the treatment of candidiasis for which they are now considered the agents of choice, as well as for other fungal infections [30]. Although resistance has been relatively rare, most recently, as a consequence of increased drug exposure, there has been an increase in development of resistance mostly in non-albicans Candida spp.…”

Section: Current Antifungal Drugsmentioning

confidence: 99%

Current Antimycotics, New Prospects, and Future Approaches to Antifungal Therapy

2020

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Fungal infections represent an increasing threat to a growing number of immune- and medically compromised patients. Fungi are eukaryotic organisms and, as such, there is a limited number of selective targets that can be exploited for antifungal drug development. This has also resulted in a very restricted number of antifungal drugs that are clinically available for the treatment of invasive fungal infections at the present time—polyenes, azoles, echinocandins, and flucytosine. Moreover, the utility of available antifungals is limited by toxicity, drug interactions and the emergence of resistance, which contribute to high morbidity and mortality rates. This review will present a brief summary on the landscape of current antifungals and those at different stages of clinical development. We will also briefly touch upon potential new targets and opportunities for novel antifungal strategies to combat the threat of fungal infections.

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“…It was shown that mortality was lowest in patients who received antifungal therapy on day 0 (15% mortality) -related to the first positive blood sample for yeasts, followed by patients who were treated on day 1 (24%), day 2 (37%), or day 3 (41%) (p = 0.0009 for trend) [98]. However, mortality and morbidity of IFIs improved over the years due to a raised awareness of fungal diseases, the development of better and faster diagnostics, the availability of appropriate antifungal therapeutics, and the growing knowledge of antifungal immunity for novel immunotherapeutic strategies [99,100]. The introduction of the echinocandins and third-generation triazoles improved the therapeutic options, yet these drugs differ from their spectrum of activity, route of administration, and bioavailability in target tissues.…”

Section: Expert Opinionmentioning

confidence: 99%

Promising immunotherapy against fungal diseases

Posch

Steger

Wilflingseder

et al. 2017

Expert Opinion on Biological Therapy

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Introduction: Despite the relatively high efficacy of antifungal drugs, invasive fungal infections (IFIs) are still associated with tremendous morbidity and mortality, since late diagnosis makes an antifungal drug therapy inefficient. Therefore, antifungal immunotherapies to specifically strengthen the host´s own immune mechanisms constitute an additional promising strategy in taking action against fungal pathogens. Areas covered: The authors summarize efforts in research and clinical trials to provide safe and efficient immunotherapeutic options against invasive fungal diseases. Treatment of IFIs is challenging as the number of available antifungals is limited and further complications include: toxicity, drug interactions and the emergence of drug resistance. Susceptibility is determined by the impaired immune status of the host. Hence, augmenting immunity by immunotherapeutic interventions may offer future directions to treat IFI. Expert opinion: A much better understanding of fungus and host cell interactions is essential for the development of safe and successful immunotherapeutic strategies. Indeed, there is encouraging preliminary data available that such approaches are possible; however, current data is too limited to allow solid conclusions on the risks and benefits in the clinical setting. Clinical trials focusing on the role of adjuvant immunotherapeutics with or without a combination of antifungals are highly needed for further evaluation. ARTICLE HISTORY

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Treatment of drug-resistantAspergillusinfection

Cited by 21 publications

References 15 publications

A Class 1 Histone Deacetylase with Potential as an Antifungal Target

A Class 1 Histone Deacetylase with Potential as an Antifungal Target

Current Antimycotics, New Prospects, and Future Approaches to Antifungal Therapy

Promising immunotherapy against fungal diseases

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