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.
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.’
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.