Cover story: The ‘antibiotic nightmare

DEFEATING THE ‘ANTIBIOTIC NIGHTMARE’

Aston University researchers have found a way of destroying an infection that can be fatal to cystic fibrosis sufferers.

Words: Annette Rubery A longside enormous challenges like Covid-19, antimicrobial resistance (AMR) is still a serious threat to global health. The term refers to the phenomenon when microorganisms such as bacteria change, rendering the drugs used to combat them useless. Along with antibiotic resistance, AMR is an ongoing problem and health professionals, from hospital nurses to GPs, are fighting it on multiple fronts. There is one bacterial pathogen, Mycobacterium abscessus, to which several academic journals have given the rare status of ‘antibiotic nightmare’. It comes from the same family that causes tuberculosis and is lethal to people with lung disorders, especially cystic fibrosis. Of the 10,000 people living with cystic fibrosis in the UK, Mycobacterium abscessus infects 13 per cent of all patients. And it’s a nightmare precisely because it’s highly drug-resistant. Treatment involves giving the patient a cocktail of aggressive antibiotics over a long period of time, a strategy which in itself may have serious side-effects. Some patients will suffer permanent hearing loss, all of them will feel very ill, and there is no guarantee that the patient will respond – in some cases, the treatment is just as damaging as the infection. Dr Jonathan Cox, who leads the Mycobacterial Research Group at Aston University, has been working on a solution to this complex set of problems with colleagues at Birmingham Children’s Hospital, and their discoveries have broken new ground. ‘Mycobacteria are very difficult to treat and cause a lot of infections,’ he explains. ‘One of

the most common that we know about is tuberculosis but there’s another type that we’ve been working with extensively in the lab: Mycobacterium abscessus. This is an environmental pathogen by origin, but it’s made the leap to humans and is now able to persist very happily within the lungs of people with cystic fibrosis and those with problems like bronchiectasis.’ The risk factors are higher with cystic fibrosis patients partly because of the ways in which they are treated. Whereas they were traditionally seen in their own homes, they are now brought together at centres of excellence where they receive specialist care. The down-side is that they can transmit infections to one another through coughing and expiration (forced exhalation of breath) and the bacteria can survive for long periods of time outside of the body, being resistant to most of the disinfectants used in the clinic. ‘There’s particularly a problem in children,’ adds Dr Cox. ‘We don’t fully understand why, but this is the reason for our collaboration with Birmingham Children’s Hospital. As you can see, there is a big opportunity here for discovering and developing new drugs.’ Dr Cox and his team first tackled the problem by looking at combinations of currently approved antibiotics which are commercially available. ‘We worked on the understanding that one antibiotic on its own won’t be enough to overpower the bacteria but you need to find what’s called synergistic antibiotics. In other words, drugs which complement each other in the way that they work.’

The team was particularly interested in antibiotics that block an enzyme – beta lactamase – which Mycobacterium abscessus contains. Beta lactamase destroys Penicillinbased antibiotics, so if the team could find something that would block it, the bacteria would, in theory, become susceptible to Penicillin again. This would open the door to a plethora of different antibiotics that might kill the infection, as well as to new treatment programmes. ‘We trialled a chemical compound called relebactam, which is a very effective beta lactamase inhibitor,’ explains Dr Cox, ‘it’s also FDA-approved and commercially available in the United States. We found it blocks this enzyme in a very powerful way. Then we wanted to find the best drug to match it with. We screened a wide variety of different Penicillin-based drugs and found the best one, by far, was amoxicillin. It is an incredibly safe, well tolerated antibiotic. This was exciting, because for the first time ever we were able to kill this highly-drug-resistant bacterial organism with Penicillin.’ The battle was not quite over, however. The amounts of relebactam and amoxicillin needed to kill Mycobacterium abscessus in the lab were still too high to give safely to patients. ‘We then looked to see if there was a third drug that we could put into the mix that would mean the concentrations of each drug was within acceptable limits. We found that if we added the antibiotic imipenem to the combination, it worked within a safe range for patients. This was great – it killed our lab strain very effectively – but the next question was, would it work in a patient?’ At the time of writing Dr Cox and his colleagues have tested the combination against 25 clinical isolates from patients of all ages, from all over the country, and they have yet to find an infection which they can’t kill with an acceptable dose. ‘At the moment we’re working with Birmingham Children's Hospital and also Heartlands and Great Ormond Street children’s hospitals to try and get this drug from Merck in the United States,’ he adds. ‘Currently it’s not manufactured in high enough quantities but over the next couple of years we expect it to be more abundantly available. Then we’ll be in a position to run a much larger clinical trial, and, assuming that meets with success, we can revolutionise the way abscessus infections are treated in future.’

Dr Jonathan Cox is a Lecturer in Microbiology in the School of Life & Health Sciences and Head of the Mycobacterial Research Group at Aston University. His research focuses on the battle against antimicrobrial resistance (AMR), mainly through the discovery of new drugs and identifying the mechanisms by which they kill bacteria.

If you are interested in supporting the work of Dr Cox and his team, please drop us a line at alumniinfo@ aston.ac.uk