Antibiotic Resistance Breakers (ARBs)

Antibiotic-resistant infections are the biggest threat to modern medicine, already costing over 700,000 lives a year globally. Without a solution, it is estimated that by 2050 that number will be closer to 10 million people every year dying from previously treatable bacterial infections.

We are investing in research to discover antibiotic resistance breakers (ARBs), which 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, including approximately 100 different antibiotics which might be combined as well as several types of bacteria to test these combinations against; it’s a mammoth task.

Our research so far

We have screened approximately 1,200 drugs from an extensive library of medicines, in combination with some of our most important antibiotics, against various strains of four multidrug-resistant bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii). These bacteria account for around 50% of major hospital-acquired infections, including sepsis (which causes 46,000 deaths in the UK each year), urinary tract infections and pneumonia.

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 ARBs. 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.

The results of this research were presented as a poster by Dr Mike Hornsey (QMUL) at the 29th European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) which took place in Amsterdam, Netherlands; view the poster.

 

Research into β-lactamase inhibitors

We funded a research project at Queen Mary’s, University of London (supervised by Dr David
Wareham) investigating the resistance-breaking activity of β-lactam broad-spectrum antibiotics (carbapenems) in combination with commercially available β-lactamase inhibitors in 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, with one antibiotic and inhibitor combination being particularly effective viz. cefepime and sulbactam.

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

The next steps

These findings have led to the launch of two new research projects.

1. Test Disc Sensitivity Kits

The next stage of testing the promising combination described above is to manufacture a test disc sensitivity kit. The discs comprise small filter paper discs that are soaked with the cefepime/sulbactam combination; these will be circulated to hospital labs around the UK. We aim to recruit 40 partner organisations, who will grow samples obtained from sick infected patients in the lab on agar (jelly) plates and place these discs onto these plates, to see if this new combination is effective at killing the bacteria.

This testing process will tell us:

  • If the results seen in one lab are reproduced in a range of labs
  • If different types (resistant species) of bacteria are equally as sensitive to the combination as current antibiotics
  • How the combination compares with other similar combinations and with other types of antibiotics
  • If there is an association between the physical and genetic characteristics of the bacteria and the test results

If the hospitals report positive results, it could lead to a new treatment against antibiotic-resistant infections. The discs could also be tested in other parts of the world, where antibiotic resistance is a bigger problem than in the UK currently. By testing the discs against samples of bacteria from individual patients with resistant infections, we can ensure that the drug combination is only used where it will be effective, reducing the risk of resistance arising to this new treatment combination. This is far superior than using broad spectrum antibiotics that are effective against many different infections to treat patients without individual testing first, as this increases the risk of new types of resistance arising and spreading.

Test disc sensitivity kits

2. Further testing

Following the screening work carried out by Public Health England, a number of new combinations were identified that could be used to develop new combination
therapies, including some that we would like to investigate further.

 

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.