Aspergillus Newsletter
January 2015

Antifungal Drug Discovery - A Review

A review by Calderone et.al. (2014) has highlighted recent data that suggests 1.3 million people worldwide now die of fungal infection - equal to or more than the number who die from TB or malaria!
 
The mortality rate of these patients is very high, something that has remained a problem despite the arrival to market of several new antifungal drugs - principally drugs that belong to a single class, azoles. New classes of drugs are needed in order to exploit new targets for therapy, but there is a lack of this type of antifungal drugs development.
 
This review discusses these problems and suggests solutions: "we focus upon antifungal drug discovery including in vitro assays, compound libraries and approaches to target identification. Genome mining has made it possible to identify fungal-specific targets; however, new compounds to these targets are apparently not in the antimicrobial pipeline. We suggest that ‘repurposing’ compounds (off patent) might be a more immediate starting point."
 
The authors then go further to encourage new techniques might be valuable additions to the search for new drugs: "Furthermore, we examine the dogma on antifungal discovery and suggest that a major thrust in technologies such as structural biology, homology modeling and virtual imaging is needed to drive discovery"
 
Despite the figures mentioned above, the market for antifungal drugs is still relatively small and needs special measures to encourage drug companies to engage in research - the current downturn in world economy has not helped, but the need of millions of people remains real, apparent and urgent.
 
For global market figures see:
 
 
News
The Aspergillus Website has been undergoing a complete restructuring - partly to allow better presentation on the increasingly important small platforms such as smartphones and tablet computers. The new structure automatically adapts to the platform the user is working with and presents content and navigation differently so as to make it easier to read and access.
 
There are several other improvements resulting from this work - users will find that they can now search for any content right from the front page - in fact any page on the website. We are able to offer better crosslinking of different content types and thus aid the user in finding all related content that is available on the website. This process continues and you will find more and more content interlinked and available, presentation improving in time.
 
One example of the greater amount of integration with social media and other popular web resources we are now able to achieve, we now offer our diary of conferences and workshops (including deadlines) as  Google calendar. Users of Google can directly integrate their calendars with our diary.
Articles
NOTE access to all articles now requires registration (free of charge)
 
(1-3)-β-d-Glucan (BDG) from cerebrospinal fluid (CSF) is a promising marker for diagnostic and prognostic aid of central nervous system (CNS) fungal infection, but its relationship to serum values has not been studied. Herein, we detected BDG from CSF at levels 2-fold lower than those in serum in patients without evidence of fungal disease but 25-fold higher than those in in serum in noncryptococcal CNS fungal infections. CSF BDG may be a useful biomarker in the evaluation of fungal CNS disease.
 
The Aspergillus fumigatus sterol regulatory element binding protein (SREBP) SrbA belongs to the basic Helix-Loop-Helix (bHLH) family of transcription factors and is crucial for antifungal drug resistance and virulence. The latter phenotype is especially striking, as loss of SrbA results in complete loss of virulence in murine models of invasive pulmonary aspergillosis (IPA). How fungal SREBPs mediate fungal virulence is unknown, though it has been suggested that lack of growth in hypoxic conditions accounts for the attenuated virulence. 
These data suggest that both A. fumigatus SREBPs are critical for hypoxia adaptation and virulence and reveal new insights into SREBPs' complex role in infection site adaptation and fungal virulence.
 
Since IL-37 transgenic mice possesses broad anti-inflammatory properties, we assessed whether recombinant IL-37 affects inflammation in a murine model of invasive pulmonary aspergillosis. Recombinant human IL-37 was injected intraperitoneally into mice prior to infection and the effects on lung inflammation and inflammasome activation were evaluated. IL-37 markedly reduced NLRP3-dependent neutrophil recruitment and steady state mRNA levels of IL-1β production and mitigated lung inflammation and damage in a relevant clinical model, namely aspergillosis in mice with cystic fibrosis. The anti-inflammatory activity of IL-37 requires the IL-1 family decoy receptor TIR-8/SIGIRR. Thus, by preventing activation of the NLRP3 inflammasome and reducing IL-1β secretion, IL-37 functions as a broad spectrum inhibitor of the innate response to infection-mediated inflammation, and could be considered to be therapeutic in reducing the pulmonary damage due to non-resolving Aspergillus infection and disease.
 
Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection(IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients.

CONCLUSIONS:

 Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification.
Reviews/Overviews
The genus Aspergillus contains etiologic agents of aspergillosis. The clinical manifestations of the disease range from allergic reaction to invasive pulmonary infection. Among the pathogenic aspergilli, Aspergillus fumigatus is most ubiquitous in the environment and is the major cause of the disease. Patients that are at risk for acquiring aspergillosis are those with an altered immune system. Early diagnosis, species identification, and adequate antifungal therapy are key elements for treatment of the disease, especially in cases of pulmonary invasive aspergillosis that often advance very rapidly. Incorporating knowledge of the basic biology of Aspergillus species to that of the diseases that they cause is fundamental for further progress in the field.
 
Survival rates among immunocompromised patients with invasive mold infections have markedly improved over the last decade with earlier diagnosis and new antifungal treatment options. Yet, increasing antifungal resistance, breakthrough infections with intrinsically resistant fungi, and potentially life-threatening adverse effects and drug interactions are becoming more problematic, especially with prolonged therapy. Evidence-based recommendations for treating invasive aspergillosis and mucormycosis provide excellent guidance on the initial workup and treatment of these molds, but they cannot address all of the key management issues. Herein, we discuss 10 general treatment principles in the management of invasive mold disease in immunocompromised patients and discuss how these principles can be integrated to develop an effective, individualized treatment plan.
Deadlines
 
 
Courses
Molecular Mycology: Current Approaches to Fungal Pathogenesis” The Marine Biological Laboratory, Massachusetts. Deadline 9th Feb 2015
 
Registration deadline is 27 February 2015.
 
Medical Mycology CPD courses Four (three-week) units of the University of Manchester Medical Mycology MSc programme are now available as Continuing Professional Development courses.
 
The first workshop on antifungal susceptibility testing in the routine laboratory will be held in the Turkish language in Ankara, Turkey, on 28 February, 2015.
Veterinary
Aspergillus fumigatus remains a major respiratory pathogen in birds and treatment is still difficult. We challenged different groups of few-day-old turkeys via intratracheal aerosolisation with increasing concentrations (10(5) up to 10(8)) of conidia using a MicroSprayer(®) device. The fungal burden was assessed by real-time PCR, galactomannan dosage, CFU counting and histopathological evaluation in order to provide a comparison of these results within each inoculum groups. Significant mortality, occurring in the first 96h after inoculation, was only observed at the highest inoculum dose. Culture counts, GM index and qPCR results on the one hand and inoculum size on the other hand appeared to be clearly correlated. The mean fungal burden detected by qPCR was 1.3log10 units higher than the mean values obtained by CFU measurement. The new model and the markers will be used to evaluate the efficacy of antifungal treatments that could be used in poultry farms.
Attention Clinicians & Scientists
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Dr Jenny LongComing Soon - Jenny Long running the London Marathon
 
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