Antibiotic Resistance Breakers (ARBs)

Antibiotic-resistant infections are the biggest threat to modern medicine. In 2019 there were 1.27 million deaths globally as a result of antibiotic resistance and a further 3.68 million deaths associated with it (The Lancet 2022). Without a solution, estimates predict that by 2050 that number will be closer to 10 million people every year. 10 million people dying from previously treatable bacterial infections.

We are investing in research to discover antibiotic resistance breakers (ARBs). ARBs are drugs that, when combined with current antibiotics, can overcome bacterial resistance. Any existing marketed drug could have this property. There are up to two thousand potential drugs for us to test with. These include approximately 100 different antibiotics which could combine with other drugs. There are also several types of bacteria to test these combinations against. It’s a mammoth task.

antibiotic resistance breakers infographic

Early Research Results

Initial results found a number of combinations of ARB and antibiotic that seem to break resistance. We tested the most promising 100 of these at different concentrations. This further screening work was undertaken at the laboratories of Public Health England (PHE). Arising from the ARB research programme we have identified nine existing drugs that could be considered antibiotic resistance breakers. The ARB hits included antimetabolites, anthracyclines, psychoactive drugs and antiseptics. Further work will be undertaken when funding allows to examine some of these hits in more detail.

Dr Charlie Hind (Public Health England) presented the results of this research as a poster at the 29th European Congress of Clinical Microbiology & Infectious Diseases (ECCMID). The event took place in Amsterdam, Netherlands in 2019. The full research findings were published in Antimicrobial Agents and Chemotherapy and a copy of the paper can be found HERE.

 

Current Research – Test Sensitivity Kits

The project aimed to recruit 40 hospital microbiology laboratories across the UK, each of which to test our new treatment, Cefepime (antibiotic) Sulbactam (inhibitor) discs, on 100 bacterial samples, collected from patients with Gram-negative* bloodstream infections. In return the labs were asked to submit their test results and bacterial samples to our partners at the University of Warwick for data/sample collation and storage.

 *Gram-negative bacteria were chosen as they account for the majority of hospital acquired antibiotic resistant infections and in 2015 contributed to approximately 5,500 deaths in England (PHE).

Whilst we were successful in recruiting 18 UK laboratories (including Chester and Wirral Microbiology Lab, James Cook University Hospital, Middlesbrough, Northern General hospital, Sheffield and others) to the trial, the study was paused as hospital microbiology labs focused on COVID-19 activities. The study resumed in Spring 2021. We prepared 18 study packs, circulated them amongst 18 labs and hospitals to date and are currently in the process of evaluating the results from the 6 labs where we have received the data sheets and isolates.

So far 537 bacterial isolates have been cultured and stored at the University of Warwick and a further 200 at Queen Mary’s London. A further 250 discs were sent overseas, though delays have meant we have not received the isolates for storage yet or the test results for analysis.

Early evidence looks promising and very exciting. Ultimately, we hope this new drug combination may lead to improved patient treatment which is a core aim of ANTRUK. This research moves us forward and discussions are under way regarding a large-scale clinical trial of Cefepime and Sulbactam.

We have also moved this study forward by awarding a contract to University College London to establish the likely dose regime of the drug combination Cefepime and Sulbactam for humans using a hollow fibre system. This is essential to determine if we move towards a large-scale clinical trial. The hollow fibre system are bunches of thin capillaries which act like the semi permeable membrane of a human blood vessel – on one side the bacteria and the other side the antibiotic. The model mimics blood flow in an infected body so that drug concentration can be altered to determine its killing effect on the bacteria. This in vitro (non-animal) research will help to establish the optimal ratio and concentration of Cefepime and Sulbactam which will clarify clinical dosing levels and likelihood for application in humans.

packets of drugs to combine into antibiotic resistance breakers

Research into β-lactamase inhibitors

We funded a research project at Queen Mary’s, University of London, supervised by Dr David Wareham. It investigated the resistance-breaking activity of β-lactam broad-spectrum antibiotics (carbapenems) in combination with commercially available β-lactamase inhibitors. Research used test tube studies with various multidrug resistant Gram-negative species.

Examples of commercially available carbapenem / β-lactamase inhibitor combinations are amoxicillin-clavulanate, ticarcillin-clavulanate and piperacillin-tazobactam.

In the Queen Mary study various carbapenem antibiotics and β-lactamase inhibitors were trialled against multidrug resistant Gram-negative bacteria to see if any previously unreported activities could be identified.

The study aimed to break resistance in up to 200 multidrug-resistant strains of the bacteria K. pneumoniae, E. coli, P. aeruginosa and A. Baumannii. Results from this programme found an unexpected interaction between combinations of β-lactamase inhibitors. One antibiotic and inhibitor combination was particularly effective: cefepime and sulbactam. The results were presented as a poster at the 29th European Congress of Clinical Microbiology & Infectious Diseases (ECCMID). The event took place in Amsterdam, Netherlands in 2019 and were subsequently published in the Journal of Antimicrobial Chemotherapy. The published paper can be found HERE

What does it mean?

  • β-lactam broad-spectrum antibiotics are a type of antibiotic that are (or were) effective against a range of bacterial infections. Examples of carbapenem antibiotics include imipenem, doripenem, and meropenem.
  • β-lactamase is an enzyme that breaks down β-lactam antibiotics, causing them not to work
  • β-lactamase inhibitors stop the enzymes from working, allowing the carbapenem antibiotic to work again

How you can help

This vital research could save lives, but testing new treatments is a costly process. We carefully select research projects that offer the highest potential return for the money invested. We are the only charity in the world dedicated to this issue, yet it could affect anyone. If you would like to contribute to our research, please consider making a donation or fundraising for ANTRUK today.