Hope on the horizon: Novel antifungal treatments in development

A review published recently describes the new antifungals that are in the pipeline that offer hope for the future.

The new drugs described in the review have novel mechanisms of action to overcome resistance, and some offer new formulations providing distinct advantages over current therapies to improve safety profiles and reduce interactions. For example, Rezafungin has shown activity against Aspergillus species and has reduced liver toxicity, better penetration and less risk of resistance.

A summary of the mechanism of action, spectrum of activity and expected benefits is provided in the paper which you can find on the Aspergillus Website. The authors have also produced a great illustration of the new antifungals and their activity so that the remaining gaps can easily be seen. Aspergillus species have been highlighted by the blue box.

It is very encouraging to see that several of the compounds have potent activity against Aspergillus species and that Ibrexafungerp, a compound affecting the fungal cell wall, has activity against several Aspergillus species and is in phase 3 clinical trials.

The potential benefits of this drug include:

  • Oral and IV formulation
  • Active against resistant strains
  • Better penetration (IAC)
  • Minimal drug-drug interactions

In addition, olorofim, VL2397 and ABA all have potent activity against Aspergillus species and are in various stages of clinical trial. All in all, there is real hope on the horizon

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‘Smart shirt’ used to monitor lung function

Hexoskin smart shirt
Hexoskin – the technology used to monitor breathing in this study

‘Smart shirts’, which are already used to measure lung and heart function in athletes, have recently been tested to determine their reliability in monitoring the lung function of healthy people performing everyday activities. The shirts were found to be reliable, giving researchers hope that they may be used in the future to remotely monitor the lung function of people with lung disease.

Smart shirts, called Hexoskin, use the stretching and contraction of the fabric to sense the volume of air inhaled or exhaled with each breath. They then send this data to an app, where it can be reviewed. The Hexoskin is comfortable and could be worn under clothing, providing an alternative to the bulky equipment traditionally used to measure breathing.

Though the technology is expensive and more work is needed, this study provides hope that the lung function of lung disease sufferers could be monitored remotely and simply by doctors. This would have the advantage that any deterioration of the condition could be recognised at an earlier stage and appropriate medical interventions could be initiated more rapidly. According to one researcher, ” Ultimately, we want to improve patients’ quality of life. If we can accurately monitor patients’ symptoms while they go about their normal activities, we might be able to spot problems and treat them sooner, and this in turn could mean less time in hospital.”

Source: ‘Smart shirt’ can accurately measure breathing and could be used to monitor lung disease

A step-change in computer power for aspergillosis genomics

Quantum supremacy

Future research in aspergillosis genetics will be (and is being) done with huge computers as they analyse entire genomes and generate huge amounts of data from the information gleaned when sequencing robots read entire genomes of complex living organisms – Aspergillus or human. The human genome contains about 3 billion base pair letters that together form a complex collection of 20-25,000 genes.

Each of these genes may be switched on or off in an infinite array of gene expression that not only makes an organism what it is but also regulates the response of a human body to external events such as infection. It is likely that mistakes in how some of these genes are expressed or how they function contribute to the reason why some of us are vulnerable to fungal infections such as aspergillosis while most of us aren’t.

Working out which of this huge number of genes is responsible for allowing fungal infection is clearly a massive task, but it is more complicated than that. If we were to sequence the genome of one person we would only get very limited information about which of their genes are fungal infection susceptibility genes. Perhaps there is more than one gene involved? As a consequence, we need to sequence the genomes of many more people who have aspergillosis in order to get a more accurate impression of the number of genes involved, and which genes are involved in permitting a fungal infection.

We also have to sequence the genomes of people who haven’t got aspergillosis so that we have something to compare the test subjects with. All in all, we will need to sequence dozens of individuals in order to arrive at reliable conclusions. This takes many months to achieve.

Computer power

Even with our most powerful computers at the University of Manchester this still takes a lot of time. Investment in Edinburgh genomic computing resources uses state of the art computer power that is 5 x faster than its predecessor, but this is just a linear progression rather than a dramatic step-change in performance likely to radically speed up the genomics work.

Additionally, however fast these computers already are, the rate of advance in computing speed will be forced to slow down as current technology will soon reach its fundamental limits – for example current computers work with ‘bits’ that represent two states – I and O so we have lots and lots of power but only the ability to work with ‘yes’ or ‘no’. This isn’t enough to process the forthcoming mass of incoming data – we need a complete step-change in how computers work to achieve fundamental accelerations in speed.

Google and quantum bits

Google, apart from being a huge company that provided services to you and I, is also a computer research company. It has been working on this fundamental limit to computer speed for some time and has just announced the successful construction of a computer that uses quantum particles rather than ‘bits’. Quantum bits can work with many more states compared with ‘bits’ so you can imagine how that might speed things up a little. Instead of ‘yes’ or ‘no’, each particle can also store ‘maybe’, ‘yes and no’ and many more – each of these new states would have taken many current bits to achieve the same end.

We can only really appreciate the huge improvement in speed this offers by setting this new computer a really difficult problem to solve – one we know will take a computer using current technology a long time to finish. Google claims that when they set a current computer a particular test problem it would take 10,000 years for it to solve it – I presume that they haven’t actually tested that using a realtime run!

Quantum supremacy


How long did the computer using quantum bits take to work out the same problem? It would be really amazing if it could do it in 100 years, incredible if it could do it in 10 years. In fact, Google claims it took just 200 seconds – truly a step-change in computer power for aspergillosis genomics.
If we are able to use that kind of computer power for genomics work in the future we would have results in fractions of a second, speeding up work on aspergillosis genomics 1000’s of times, making it theoretically possible we could be doing complete genome checks in a single visit to the clinic in the future.

https://www.bbc.co.uk/news/science-environment-50154993

Vitamin D deficiency may increase amphotericin B-related kidney toxicity

Graph showing that mice with vitamin D deficiency had more kidney toxicity from amphotericin B

Do you take vitamin D supplements over winter?

Current NHS/PHE guidelines say that all adults should consider taking vitamin D supplements between October and March, or all year round if they are at risk of deficiency (e.g. people who have darker skin, or spend most of their time indoors or covered up).

But a new study suggests it might be even more important for people living with aspergillosis. Ferreira et al 2019 found that mice with a vitamin D deficiency experienced more kidney toxicity when given amphotericin B (lipid formulation). Click here to read more here.

If you haven’t had your levels tested recently, it might be worth getting your doctor to check them.

When taking vitamin D supplements:

  •  For best absorption, take it with a meal containing fat and calcium
  •  Check the label for the dosage – it should be 10-25 mcg per day, or 400-1000 IU (don’t rely on % RDA/NRV)
  •  There are two forms: D3 (cholecalciferol) is more effective than D2 (ergocalciferol)

For more information on Vitamin D guidelines:

Aspirin may reduce harmful effects of air pollution on lungs

A recent study by Dr Xu Gao and colleagues has looked at the relationship between lung function and the use of non-steroidal anti-inflammatory drugs (which include aspirin) in 2,280 veterans. The researchers then compared this with air pollution data from the previous month in their hometown of greater Boston. Other factors, including whether or not the participant was a smoker were also taken into consideration.

The study found that NSAIDs nearly halved the effect of particulate matter (all solid and liquid particles suspended in air) on lung function. The mechanism by which this protection happens is unknown, but may be due to NSAIDS reducing inflammation in the lung caused by pollution. As most of the participants in the study were taking aspirin, this effect was deemed to be predominantly due to aspirin, but the effect of other NSAIDs would be useful to study.

These results show that aspirin may be useful in the short-term protection of lungs against air pollution. However, air pollution contributes to a number of other harmful bodily effects so it is still important to minimise overall exposure.

To check air pollution in your area, click here

References:

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