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Sustainability & Environment

Scientists studying DNA in soil samples from Svalbard in the High Arctic have discovered a surprisingly large number of clinically-important antibiotic resistance genes. In total, 131 antimicrobial resistance genes were identified, while five out of eight sites had abundant multidrug resistance genes.

 The Svalbard Islands

The Svalbard Islands are in Northern Norway.

The finding is all the more unexpected as the team was seeking a virgin environment to try and establish what a background level of antimicrobial resistance in soil bacteria looks like. 

 soil bacteria

Scientists found genes important to antimicrobial resistance in soil bacteria.

‘We took 40 samples to give us an idea of what the baseline of resistance might look like in nature, but we were surprised by how different the sites were from each other,’ says lead scientist David Graham at Newcastle University. Areas with high wildlife or human impact had greatest diversity of resistance DNA in the soil.

The results show that antibiotic resistance genes are accumulating even in the most remote locations. Included in a number of samples was a multidrug resistant gene called New Dehli strain, first isolated in India.

Newcastle University find antibiotic resistant genes in Arctic. Video: Newcastle University

Some sites had levels of antimicrobial resistance 10 times greater than others, particularly those with elevated levels of phosphorus, a nutrient usually scarce in Arctic soils. 

‘There was much greater resistance diversity in sites with strong signatures of faecal matter,’ says Graham, indicating that migratory birds most likely brought the antimicrobial resistance genes, depositing them via their guano.


Careers

Each year SCI’s Scotland group runs a competition where students are invited to write a short article describing how their PhD research relates to SCI’s strapline: where science meets business.

Jack Washington (right), a Pure and Applied Chemistry PhD student at the University of Strathclyde, was the overall winner of this year’s competition. His article ‘Clavulanic acid - The fight against antibiotic resistance’ is reproduced here:

Clavulanic acid - The fight against antibiotic resistance

 The molecular structure of clavulanic acid

The molecular structure of clavulanic acid. Image: Wikimedia Commons

If you were to say that cancer is the biggest threat to public health you would be wrong.

One of the most pre-eminent risks to human existence is antibiotic resistance. Antibiotics are medicines used to fight bacterial infections. However, bacteria are fighting back at an alarming rate. Without effective antibiotics, we could live in a world where infections borne from a simple wound could be deadly. Routine surgeries would no longer be possible. Whilst this bacterial apocalypse seems drastic, it’s a very real possibility, and one we could face in the near future.

 Alexander Fleming

Alexander Fleming. Image: Wikimedia Commons

Antibiotics are part of a multibillion-pound industry and are essential for life as we know it today. In 1928, the scientist Alexander Fleming, from Ayrshire in Scotland, serendipitously discovered penicillin. This chance discovery revolutionised the treatment of bacterial infections and spurred a wealth of antibiotic research. 88 years later, in the nearby town of Irvine, I started my PhD project in this field.

Penicillin is a β-lactam antibiotic, which made up of molecules containing a chemical entity known as a β-lactam. This β-lactam is a covalent warhead – a harpoon that grips its bacterial victim and doesn’t let go. This harpoon interrupts bacterial cell wall formation, causing the bacteria to rupture and die. 

Maryn McKenna: What do we do when antibiotics don’t work any more? Video: TED

However, bacteria can retaliate by producing aggressive enzymes that destroy this warhead. Another member of the β-lactam family, clavulanic acid, can thwart these enzymes. Clavulanic acid has weak antibiotic activity on its own so is used in a double act with another antibiotic, amoxicillin, to fight antibiotic-resistant bacteria as a team.

 

Health & Wellbeing

Around 700,000 people worldwide die every year from bacteria that have developed resistance to antibiotics. In the UK alone, that figure is at least 12,000 – more deaths than from breast cancer. And those numbers look set to rise even higher.

‘It’s not just the fact that resistance is increasing – that’s inevitable,’ says Nick Brown, Director of advocacy group, Antibiotic Action. ‘The issue is more the rate of increase in resistance, which appears to be accelerating.’

The Infectious Diseases Society of America recently reported resistance to drugs within six months of antibiotics coming onto the market, and in some cases, even before the drug goes on the market. Many bacterial strains are increasingly displaying resistance to combinations of commonly used and last-resort antibiotics.

 antibiotics

Of 33 antibiotics in development targeting priority pathogens, just nine belong to five new antibiotic classes. Image: Public Domain Pictures

‘The end of the antibiotic era isn’t on the horizon just yet,’ Brown says. ‘But we can see it wouldn’t take much to get that way.’

Failure to tackle antibiotic-resistant superbugs could result in 10m deaths a year by 2050, according to the UK government-commissioned Review on Antimicrobial Resistance. The UN and G20 have both made political commitments to combat the problem. Nevertheless, time is running out.

‘This is an urgent and rapidly rising global health problem,’ says Ghada Zoubiane, science lead for the Wellcome Trusts’ drug-resistant infections team. ‘We need greater investment in developing new ways to treat and protect people from these deadly infections and we need better understanding of how resistance spreads.’

 

What causes antibiotic resistance? Video: TED-Ed

Despite calls for increased R&D, no new classes of antibiotics have been approved since the early 1980s, apart from the approval of linezolid in 2000, and the last new class to treat Gram-negative bacteria was discovered in 1962, Zoubiane says.

Big pharma withdrew en masse from the antibiotic space in the 1990s, due to the low returns on the high level of investment required in antibiotic R&D. Recognising the urgency of the problem, however, in January 2016 more than 90 pharma and biotech companies committed to enhancing antibiotic discovery.

The move has been accompanied by more research into understanding resistance mechanisms, as well as a shift to more outside-of-the-box thinking about alternative treatments.

 microscope

In 2016, over $500m was invested into research into antibiotic resistance. Image: PxHere

In February 2017, the World Health Organization (WHO) published its list of 12 antibiotic-resistant ‘priority pathogens’ that pose the greatest threat to human health. Most notable are the Gram-negative bacteria, which possess an additional outer cell membrane and are harder to treat with antibiotics than Gram-positive bacteria.

‘These bacteria have been assessed as the most critical priority for antibiotic R&D, as strains are emerging worldwide that cannot be treated with any of the antibiotics currently on the market,’ WHO says.

bacteria gif

Originally posted by amnhnyc

Despite the increased commitment to R&D, however, a WHO report in September 2017 lamented the ‘serious lack of new antibiotics under development’. Among the 33 new chemical entity antibiotics in development targeting priority pathogens, just nine belong to five new antibiotic classes.

There are 16 products, both antibiotics and biologics, with activity against one or more Gram-positive priority pathogens – although mostly targeting methicillin-resistant Staphylococcus aureus (MRSA) – including two new antibiotic classes.

Meanwhile, ‘the situation is worse for Gram-negative bacterial infections’, says WHO. Of ten products in Phase 1 trials, ‘almost all the agents are modifications of existing antibiotic classes […] active only against specific pathogens or a limited subset of resistant strains’.

The 2016 Lister Memorial Lecture: Dame Sally Davies on Global antiiotic resistance. Video: SCI

WHO warns that ‘more investment is needed in basic science, drug discovery and clinical development, especially for the critical priority Gram-negative carbapenem-resistant pathogens P. aeruginosaA. baumannii, and Enterobacteriaceae.’

‘We need to find a strategy not to overcome resistance, but to be able to live with and manage it,’ Brown reflects. ‘I’m more optimistic than some. It’s important to remember that before antibiotics were discovered, the human race didn’t die out.’


Antimicrobial drug discovery

 bacteria pertri dish

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Health & Wellbeing

Some could argue the greatest threat to life as we know it is the slow, invisible war being fought against antibiotic resistant bacteria. The accidental discovery of penicillin by Fleming in the late 1920s revolutionised modern medicine, beginning with their use in the Second World War.

Over-prescription of these wonder drugs has allowed bacteria, which multiply exponentially, the ability to pick up on deadly cues in their environment at a phenomenal rate. They’re adapting their defence mechanisms so they’re less susceptible to attack. In theory, with an endless supply of different drugs, this would be no big deal.

 Alexander Fleming

Alexander Fleming, who discovered penicillin. Image: Wikimedia Commons

Unfortunately, the drug pipeline seems to have run dry, whilst the incidence of resistance continues to climb. For the gnarliest of infections, there’s a list of ‘drugs of last resort’, but resistance even to some of these has recently been observed. A report published by the World Health Organisation echoes these warnings – of the 51 new drugs in clinical development, almost 85% can be considered an ‘upgraded’ version of ones on the market right now. These drugs are a band aid on a snowballing problem.


Are viruses the answer?

Bacteriophages, or phages for short, are viruses that infect only bacteria, wreaking havoc by hijacking cellular machinery for their growth and development.

 A bacteriophage

A bacteriophage. Image: Vimeo

Phages can find themselves in one of two different life cycles: virulent and temperate. The first involves constant viral replication, killing bacteria by turning them inside out (a process known as lysis). The second life cycle allows the phage in question to hitch a ride in the cell it infects, integrating its genetic material into the host’s and in doing so, propagating without causing immediate destruction. It’s the former that is of value in phage therapy.

Long before Fleming’s discovery, phages were employed successfully to treat bacterial infections. In areas of Eastern Europe, phages have been in continuous clinical use since the early part of the 20th century. 

Why did their use not take off like that of penicillin’s in the West? ‘Bad science’ that couldn’t be validated in the early days proved to be disheartening, and phages were pushed to the wayside. Renewed interest in the field has come about due to an improvement in our understanding of molecular genetics and cell biology.

Phage gif

Originally posted by futuristech-info

Phages are highly specific and, unlike antibiotics, they don’t tamper with the colonies of bacteria that line our airways and make up a healthy gut microbiome. As they exploit an entirely different mode of action, phages can be used as a treatment against multiple drug-resistant bacteria. 

Repeated dosing may not even be necessary – following initial treatment and replication of the phage within infected cells, cell lysis releases ever more phages. Once the infection is cleared, they’re excreted from the body with other waste products.


What is holding it back?

A number of key issues must be ironed out if phage therapy is to be adopted to fight infection as antibiotics have. High phage specificity means different phage concoctions might be needed to treat the same illness in two different people. Vast libraries must be created, updated and maintained. Internationally, who will be responsible for maintenance, and will there be implications for access?  

Scientists are looking at new ways to tackle antibiotic resistance. Video: TEDx Talks

Despite proving a promising avenue for (re)exploration, under-investment in the field has hindered progress. Bacteriophage products prove hard to patent, impacting the willingness of pharmaceutical companies investing capital. AmpliPhi Biosciences, a San Diego-based biotech company that focuses on the ‘development and commercialization of novel bacteriophage-based antibacterial therapeutic,’ was granted a number of patents in 2016, showing it is possible. This holds some promise – viruses might not save us yet, but they could be well on their way to.