Friday, 11 July 2014

Amphibians 'Learn' to Avoid Pathogenic Fungi

There is some data that supports the impression that fungi are causing increasing numbers of fatal infections in the wild over a large part of the world. Worryingly many completely different groups of organisms seem to be in decline e.g. bats, corals (Aspergillus sydowii), bees, snakes and amphibians but also plants. Some of this has been suggested to be a result of global warming - environments are changing as temperatures shift and those organisms trapped in a warmer environment are stressed to such an extent that they are more vulnerable to infection or predation. Some is being suggested to be a result of human activity spreading pathogens to parts of the world that they had not reached before now.

Aside from the importance of each species with respect to itself and the global diversity of living organisms, many of these species are of fundamental economic importance to us all so we need to understand why these populations are declining so as to be able to stop and reverse the decline.

Osteopilus septentrionalis
This new paper in the highly important journal Nature offers us one clue on how amphibians may be helped to start to resist pathogenic fungi. This particular group of frogs are living in an environment that has become infested with a pathogenic fungus (Batrachochytrium dendrobatidis). Conservationalists have taken frogs away from the infested areas and bred them successfully in captivity, however when they re-introduce them to the infected areas they fail to thrive - after all the fungus is still there so we might predict this outcome.

How can we help?

It turns out that if you expose the frogs to the fungus two things happen to enable resistance: they quickly learn to avoid it, and gradually become immune. This happens whether or not the fungus is alive. If then we carefully expose the frogs to dead fungus prior to re-release into the wild they should be able to avoid the fungus and thus thrive more readily. Perhaps other organisms have similar survival strategies we can use to help protect them?

The authors put it like this:
these results offer hope that other wild animal taxa threatened by invasive fungi might be rescued by management approaches based on herd immunity.

Tuesday, 8 July 2014

Aspergillus On List of Qualifying Pathogens

Continuing on our recent theme of finding ways to encourage the delivery of new antibiotic and antifungal drugs, in the US the government is taking action by offering a series of incentives to manufacturers including an extra five years of exclusivity during which the original manufacturer is the ONLY permitted source of the new medication. Hopefully this will encourage new products as the potential for profit is consequently increased.

Happily and importantly for those living with fungal infections such as aspergillosis the causal organism of aspergillosis Aspergillus has been added to this US government list of qualifying pathogens.


The Food and Drug Administration (FDA or Agency) is issuing a regulation to establish a list of ‘‘qualifying pathogens’’ that have the potential to pose a serious threat to public health. This final rule implements a provision of the Generating Antibiotic Incentives Now (GAIN) title of the Food and Drug Administration Safety and Innovation Act (FDASIA).
GAIN is intended to encourage development of new antibacterial and antifungal drugs for the treatment of serious or life- threatening infections, and provides incentives such as eligibility for designation as a fast-track product and an additional 5 years of exclusivity to be added to certain exclusivity periods. 
Based on analyses conducted both in the proposed rule and in response to comments to the proposed rule, FDA has determined that the following pathogens comprise the list of ‘‘qualifying pathogens:’’ Acinetobacter species, Aspergillus species, Burkholderia cepacia complex, Campylobacter species, Candida species, Clostridium difficile, Coccidioides species, Cryptococcus species, Enterobacteriaceae (e.g., Klebsiella pneumoniae), Enterococcus species, Helicobacter pylori, Mycobacterium tuberculosis complex, Neisseria gonorrhoeae, N. meningitidis, Non-tuberculous mycobacteria species, Pseudomonas species, Staphylococcus aureus, Streptococcus agalactiae, S. pneumoniae, S. pyogenes, and Vibrio cholerae. 
The preamble to the proposed rule described the factors the Agency considered and the methodology used to develop the list of qualifying pathogens. As described in the preamble of this final rule, FDA applied those factors and that methodology to additional pathogens suggested via comments on the proposed rule.
DATES: This rule is effective July 7, 2014.
Original document 

Monday, 7 July 2014

Aspergillus Metabolite Overcomes Antibiotic Resistance

It is well documented that shortly after the arrival of antibiotics came the response from bacteria - antibiotic resistance that renders the original antibiotics useless. There are several mechanisms that bacteria can use to become resistant and one of the major systems used is to produce enzymes (β-lactamases) that directly attack the chemical structure of some antibiotics, destroying them.

It is clear that we need to keep resistance under control and there have been several strategies to manage this resistance including limiting the use of antibiotics, better prevention of infection and encouraging the patient to use the full course of prescribed antibiotic.

These strategies have only been partly effective and there is an ever more urgent need to provide new antibiotics - a fact that is being recognised by our political leaders recently.

Happily there are other ways to defeat resistance and this research group working in Ontario, Canada & Cardiff, Wales have exploited one such alternative by rendering what were resistant bacteria sensitive to antibiotics once more by inhibiting the β-lactamase activity.

Quoting from their paper:
The β-lactams (penicillins, cephalosporins, carbapenems and monobactams) are one of the most important and frequently used classes of antibiotics in medicine and are essential in the treatment of serious Gram-negative infections.
Since the clinical introduction of penicillins and cephalosporins over 60 years ago, the emergence of β-lactamases, enzymes that hydrolyse the β-lactam ring that is essential for the cell-killing activity of the antibiotics, has been an ongoing clinical problem1.
Antibiotic resistance has intensified medicinal chemistry efforts to broaden antibacterial spectrum while shielding the core β-lactam scaffold from β-lactamase-catalysed hydrolysis. The result has been multiple generations of β-lactams with improved efficacy and tolerance to existing β-lactamases. However, pathogenic bacteria have in turn evolved further resistance mechanisms primarily by acquiring new or modified β-lactamases. This is typified by the emergence of extended spectrum β-lactamases that inactivate many of the latest generation cephalosporins and penicillins (but not carbapenems)2.
Consequently, the past two decades have seen substantial increases in the utilization of carbapenems such as imipenem and meropenem. Predictably, this increase in carbapenem consumption has been accompanied by the emergence of carbapenem-resistant Gram-negative pathogens (CRGNP)3, 4. In particular, carbapenem-resistant Enterobacteriaceae (CRE) is a growing crisis across the globe5 as witnessed by recent outbreaks in Chicago6 and British Columbia7.
The acquisition of metallo-β-lactamases (MBLs) such as NDM-1 is a principle contributor to the emergence of carbapenem-resistant Gram-negative pathogens that threatens the use of penicillin, cephalosporin and carbapenem antibiotics to treat infections. To date, a clinical inhibitor of MBLs that could reverse resistance and re-sensitize resistant Gram-negative pathogens to carbapenems has not been found.
Here we have identified a fungal natural product, aspergillomarasmine A (AMA), that is a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp. possessing either VIM or NDM-type alleles. In mice infected with NDM-1-expressing Klebsiella pneumoniae, AMA efficiently restored meropenem activity, demonstrating that a combination of AMA and a carbapenem antibiotic has therapeutic potential to address the clinical challenge of MBL-positive carbapenem-resistant Gram-negative pathogens.
NOTE: Aspergillomarasmine is a natural product of Aspergillus oryzae. This is one more example of fungi providing help in our battles against bacterial infection.

Friday, 4 July 2014

$32 million for New Antifungal Drug Development & New Antifungal Treatment Strategies

K2 therapeutics was only founded 2 years ago in San Diego, California with $6 million funding and has successfully developed a candidate for a new antifungal drug referred to as Biafungin. Much is unknown outside the company about this new compound but early testing has provided sufficient encouragement for new investors to fund a further $32 million.

Enhanced stability of Biafungin

A principle advantage of this compound over drugs already beign used include its very long half life - this should allow it to be given only once per week instead of daily IV doses currently necessary for the most recently developed echinocandin Anidulafungin. This will save on costs for hospitals, minimise infection potential and make life more pleasant for the patient - it may also be a useful alternative to azole drugs for those patients who cannot take azoles.

Biafungin is an echinocandin, so it would be a useful addition if it gets through to market as we are beginning to see significant resistance developing to azole antifungals in many clinics that treat serious fungal infections such as aspergillosis. There are however several barriers to this new compound becoming a useful drug  as it has to go through several stages of clinical testing first, but clearly its investors think it is showing enough potential for them to take the risk! Phase 1 trials begin in 2015.

K2 have also developed a second compound named 'Cloudbreak' that seems to improve the targeting of parts of our immune system to enable a more active attack on a fungal infection. If this is confirmed using in vivo experiments it will be a novel approach to treating fungal infections, potentially offering a completely new weapon in the war against Aspergillus and other invading fungi.

K2 therapeutics have become Cidara Therapeutics Inc. as a result of this investment.

Thursday, 3 July 2014

A New Way to Fund Orphan Drug Discovery

Orphan drug development is more difficult to fund as they tend to be required for the treatment of diseases that are rare compared with illnesses such as heart disease, asthma etc - such as to treat aspergillosis. If the market for these drugs is small then there is likely to be difficulty getting an adequate return on sales to cover the huge cost of development - at the very least there is a high risk of little or no profit so drug companies cannot find financial backers. 

This recent article offers the possibility of a new type of funding for these drugs: Megafunding.

Quoting Drug Discovery Today journal:

In the face of pharmaceutical industry productivity decline over the past several years, the authors of an article published in Drug Discovery Today propose a novel method of financing drug discovery. Fagnan et al. introduce the concept of ‘megafunds’ to attract investments into risky orphan drug research and development projects. A megafund would raise funds by issuing ‘research-backed obligations’ (RBOs), i.e. bonds on potential revenues from future sales of orphan drugs and intellectual property. Instead of relying on venture capitalists and other investment funds, megafunds could attract capital into orphan drug portfolios from a much larger investor base, usually unable to invest in early-stage drug discovery.
Based on their simulations and the assumption of high success rates, the authors suggest that megafund portfolios containing ten to twenty investigational compounds could deliver potentially, albeit uncertain, high returns on investment. While Fagnan et al. admit their simulations are only indicative of megafund potential, they maintain that novel financing models, such as RBOs to constitute megafunds, should be developed to address growing drug discovery challenges. By pooling and diversifying resources, the authors believe that megafunds spread their risk and offer greater financial flexibility whilst ensuring more efficiency and lower drug development costs.

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