Paul Chapman, Partner at Marks & Clerk LLP, takes a look at research underway for testing a compound on Gram-negative bacteria known for being the most difficult to treat of all infections
It was welcome news to hear that scientists had recently discovered a new compound that could pave the way for much-needed new treatments in the fight against superbugs. However, the path from initial discovery to the commercialisation of a drug is a long and complex one — perhaps even more so for new antibiotics.
Despite being top of the World Health Organization’s list of pathogens for which new medicines are desperately needed, there have been no fresh treatments forthcoming in the battle against Gram-negative bacteria during the last five decades, including pathogenic E. coli —a multidrug-resistant pathogen said to be responsible for millions of antibiotic-resistant infections worldwide annually.
Indeed, no potential drugs for targeting Gram-negative bacteria have entered clinical trials since 2010, representing a worrying drop against the backdrop of a global crisis.
Gram-negative bacteria are becoming increasingly resistant to existing antibiotics and can cause severe and often deadly illnesses such as pneumonia, urinary tract infections and bloodstream infections.
They pose a particular threat in hospitals and nursing homes, among patients who need devices such as ventilators and catheters, etc., and are particularly difficult to treat because the cell wall of the bacterium acts as a barrier to prevent drugs from successfully getting into the microbe and exerting their beneficial effect.
The scale of the antimicrobial resistance (AMR) problem is clear. It is already responsible for 25,000 deaths in the EU, annually, and it’s estimated that, by 2050, more than 10 million people could die every year because of antibiotic-resistant infections unless the threat is addressed.
Aiming to tackle that issue — arguably one of the biggest public health challenges of our time — researchers all over the world have been seeking out novel ways to target and fight multidrug-resistant bacteria more effectively.
Now, the Sheffield University team’s discovery has offered tangible hope after they studied the structures of anticancer drugs based on ruthenium, a rare metal. The team tweaked the structure of the metal-based compounds to see if they had antimicrobial properties and ended up with something that was toxic towards bacteria, particularly Gram-negative bacteria, but not toxic towards humans. Significantly, it’s thought that this new compound also kills Gram-negative E. coli.
The compound seems to have several modes of action, making it more difficult for resistance to emerge in the bacteria. Furthermore, the breakthrough could lead to vital new treatments against life-threatening superbugs and the growing global risk posed by AMR. At the moment, the research team know only that the new compound is effective against some strands of antibiotic-resistant bacteria … but they believe that it may be able to attack other bacterial strands as well.
The team will now look at how the compound fares in mammals before embarking on human studies. Their timing could be crucial. Although a class of antibiotics called carbepenems are often used for the treatment of Gram-negative bacteria, infections that are resistant to these therapeutics are beginning to emerge.
Enhanced research of the kind undertaken in Sheffield continues to have a very clear and important role to play in combating so-called superbugs, but greater education and the development of existing and new medtech must be considered of vital importance too. Quite often, better point of care (POC) testing, in combination with new antibiotics, is the best form of attack.
AMR and the associated issues — an over-prescription of antibiotics, costs applied an under-pressure health service, an unrealistic expectancy from the public and the routine use of antibiotics in livestock farming – have of course been well publicised.
There is a great deal of work going into combatting this key healthcare challenge for our time. Much commendation must go to those seeking to develop the next generation of antibiotics as the development of novel alternatives is essential to provide a last line of defence against rapidly evolving pathogens.
The testing of metal-based compounds for antimicrobial properties is also to be lauded for its innovative thinking. Indeed, the particular compound being tested by Sheffield University is luminescent … so it glows when exposed to light. This means that the uptake and effect on bacteria can be followed by advanced microscope techniques.
However, in aiming to reduce inappropriate prescription of existing antibiotics, we must also consider the importance of POC testing and more technologically advanced diagnostic tools.
Suitable point-of-care diagnostics are important in terms of extending the period of time for which existing antibiotics will be effective and, in essence, for buying fresh time to develop new ones. Once we have new antibiotics, then, hopefully, existing diagnostics can still be used to maintain their longevity.
At Marks & Clerk, we file a lot of patents in the diagnostics field and continue to monitor sector developments. In terms of combatting AMR, many new diagnostic tools are being developed, which is encouraging to see. Doctors represent a vital front line in this battle. However, they are often put under severe pressure from patients to be prescribed something.
Having a suitable test that would clearly show the absence of a bacterial infection would undoubtedly assist doctors in reassuring patients and backing up their assertion that they should not be prescribed antibiotics.
Of course, in the scenario of an infection being potentially life threatening, it is of paramount importance to treat the patient quickly and, sometimes, the doctor has little option but to prescribe antibiotics, at least initially. Providing medical professionals with the correct tools will help to ensure that antibiotics are used only when appropriate and necessary.
One thing that is becoming increasingly clear is the importance of the cost of any diagnostic test. Antibiotics can be bought on the street, very cheaply in some countries; so, if a test is not cheaper than the antibiotics themselves, it may be difficult to adopt test use.
Point of care diagnostics and antibiotic development need to go hand in hand. A great deal of effort, time and resource is put into the research and development of both POC testing and diagnostic technologies to ensure medical professionals only give antibiotics when it is appropriate to do so, which will slow down antibiotic resistance from developing in the first instance.
Without POC diagnostics and antibiotic development, some patients will continue to receive existing antibiotics unnecessarily, increasing the likelihood of AMR developing.
New treatments for Gram-negative bacteria must also be targeted, just as Sheffield University has done. Indeed, the World Health Organization recently stated that new treatments for these bacteria were “Priority 1 Critical” because they cause infections with high death rates and are rapidly becoming resistant to all present treatments.
Essentially then, we need heightened innovation across the board — bolstered by the vital protection that early securing of intellectual property (IP) affords, which in turn helps to commercialise and incentivise investment in the development of new antimicrobials — but we also need major behavioural changes.
The honing of a strong IP portfolio is often the foundation of successful commercialisation. However, a carefully balanced approach to new antibiotic development, alongside the POC testing of infections, can hopefully go some way towards turning the tide and avoiding the nightmare superbug scenario.