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. 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. 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.
The world’s largest agriculture companies have joined forces to invest in new and innovative technologies that will hopefully eradicate malaria by 2040. The ‘Zero by 40’ campaign was launched at the annual Commonwealth Heads of Government meeting held in London last week.
The programme has the support of the Bill & Melinda Gates Foundation and the Innovative Vector Control Consortium, based in Liverpool, UK, as well as companies BASF, Bayer, and Syngenta – among others.
Mosquitos are known vectors of the malaria virus. Image: James Gathany/Centre for Disease Control
Malaria affects over 200 million people each year – most cases are found in Africa but the disease is still prevalent in South East Asia and in the Mediterranean. Although the number of cases has been slowly falling year-on-year, this progress is threatened by insecticide resistance.
It is estimated that four out of five malaria cases have been prevented through long-lasting insecticide-treated bed nets (LLINs) and indoor residual spraying (IRS) techniques. The campaign is a continued sign of commitment from the agriculture industry, with companies already having produced innovative solutions to tackle the global issue.
Both Syngenta and Bayer have introduced new IRS products – either in the final stages of development or already employed across Africa. BASF has developed a new generation mosquito net with an insecticide derived from crop use to deter resistant mosquitos.
Insecticides used in agriculture are used as control mechanisms for the mosquito population.
‘Our industry collaboration, supported by our funders including the Bill & Melinda Gates Foundation and the UK’s Department of International Development, is starting to bear fruit and is saving lives today,’ said Nick Hamon, CEO of IVCC.
‘But we still have a long way to go to achieve our ambition of ending the disease burden of malaria by 2040,’ Hamon said. ‘This new initiative will not only secure the current supply of solutions, but will pave the way for desperately needed new forms of chemistry and new vector control tools to reduce the disease burden of malaria which still affects millions of people.’
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.
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.
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.
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. aeruginosa, A. 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
Tweaking the chemical structure of the antibiotic vancomycin may offer a new route to tackle the burgeoning problem of antibiotic-resistant bacteria, researchers in Australia have discovered.
Vancomycin has been used since the late 1950s to treat life-threatening infections caused by Gram-positive bacteria, including methicillin-resistant S. aureus (MRSA). The antibiotic works by binding to a precursor of the cell wall component, peptidoglycan, Lipid II, thus inhibiting bacterial growth.
Lipid II is present in both Gram-positive and Gram-negative bacteria. However, in Gram-negative bacteria it is protected by an outer membrane. In Gram-positive bacteria, Lipid II is embedded in the cell membrane but part of the molecule – a pentapeptide component – sticks out, which is what vancomycin binds to.
The researchers at the University of Queensland’s Institute for Molecular Biology (IMB), led by director of superbug solutions Matt Cooper, reasoned that if they could increase the ability of vancomycin to bind to the bacterial membrane, this would make it more difficult for bacteria to develop resistance to it.
‘Our strategy was to add components to vancomycin so that the new derivatives – which we call “vancapticins” – could target more widely the membrane surface,’ explains Mark Blaskovich, senior research chemist at IMB. ‘By providing two binding sites – the membrane surface and the membrane-embedded Lipid II - this allows binding to resistant strains in which the Lipid II has mutated to reduce interactions with vancomycin.’
In addition, the researchers say that the vancapticins have been designed to take advantage of compositional differences between mammalian and bacteria cell membranes – ie bacterial cells have a greater negative charge. The vancapticins have greater selectivity for bacterial cells over mammalian cells, potentially reducing off-target effects and giving a better safety profile. A series of structure–activity studies showed that some of the vancapticins were more than 100 times more active than vancomycin.
Hospital-Associated Methicillin-resistant Staphylococcus aureus (MRSA) Bacteria. Image: NIAID
This membrane-targeting strategy, the researchers say, has the potential to ‘revitalise’ antibiotics that have lost their effectiveness against recalcitrant bacteria as well as enhance the activity of other intravenous-administered drugs that target membrane associated receptors.
John Mann, emeritus professor of chemistry at Queen’s University Belfast, UK, comments: ‘Bacteria have developed numerous strategies to modify the binding, uptake and expulsion of antibiotics, and thus develop resistance. So, it is especially exciting to see the development of these new vancomycin derivatives that enhance the membrane binding properties of the antibiotic, thus enhancing its efficacy and beating the bacteria at their own game.’
Cassie Sims is a PhD researcher at Rothamsted Research in Harpenden, UK. Photo: Rothamsted
Rothamsted Research is the oldest agricultural research station in the world – we even have a Guinness World Record for the longest running continuous experiment! Established in 1843, next year we celebrate our 175th anniversary, and as a Chemistry PhD student at the institute today, I can’t wait to celebrate.
Wheat samples from the record-breaking Broadbalk experiment. Photo: Cassie Sims
Rothamsted is known for many amazing scientific accomplishments, and it has a rich history, which I have explored through many of the exhibitions put on by the institute for the staff every month or so.
One of the old labs set up for the exhibitions we hold at Rothamsted. Photo: Cassie Sims
Working in what was the Biological Chemistry department, I am following in the footsteps of Chemists such as Michael Elliott, who developed a group of insecticides known as pyrethroids. These are one of the most prolific insecticides used in the world, still widely used today and researched here at Rothamsted – in particular, the now-prevalent insecticidal resistance to them.
I was privileged to view an exhibit of Michael Elliott’s medals late last year at Rothamsted – one of the opportunities we are given as staff here. Recently, I was also able to view a collection of calculators and computers from the earliest mechanical ones, to Sir Ronald Fisher’s very own ‘Millionaire’ Calculator, which could multiply, add and subtract entirely mechanically.
Sir Ronald Fisher’s ‘Millionaire’ Calculator. Photo: Cassie Sims
In more recent times, Rothamsted has had an update (a little more than a lick of paint) with newer buildings, labs and equipment constantly being added. My office and lab are situated in the architecturally interesting Centenary building, which was built only 10 years ago. Some of the research has had an update too – plant science research is a bit more focused on molecular biology these days, and our chemistry has been significantly advanced over the last century by advances in analytical equipment.
A few years ago, Rothamsted was briefly the centre of media attention due to a ‘controversial’ GM field trial testing wheat made to emit (E)-β-farnesene, the aphid alarm pheromone, and whether the plants could repel aphids.
…they couldn’t, but this was one of the first type of GM trials of its type, and it was an interesting study that combined many disciplines of science, from molecular biology and plant science, to entomology and chemical ecology.
Rothamsted is not just about science, either – we have a few longstanding social traditions such as Hallowe’en parties and Harvest Festival, not forgetting of course my favourite; our summer Sports Day, which provides much entertainment in the form of serious research scientists participating in sack races to win some outstandingly tacky trophies. We also have an onsite bar (if that is what you could call it), which is a little more like a converted cricket club, and serves as a venue for most events, and has been the location of many of my great memories.
If I had to describe being a student at Rothamsted in one word, it would be weird! There is a lot of fun to be had, but we are also surrounded by an incredible history that we cannot forget as we forge a new path in our fields (literally and scientifically!).
I hope one day that I can leave some kind of mark here – but even if not, I will be happy to have been part of such a prestigious institute and to have worked alongside such great scientific minds.
What are the sustainability challenges being tackled by researchers at Rothamsted? Sir John Beddington, Chair of the Rothamsted Research Board gave this talk at SCI in London in September – part of our ongoing programme of free-to-attend public evening lectures.
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, 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. 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.
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.