New resistance-busting antibiotic combination could extend the use of ‘last-resort’ antibiotics
Scientists have discovered a new potential treatment that has the ability to reverse antibiotic resistance in bacteria that cause conditions such as sepsis, pneumonia, and urinary tract infections, according to a report from the World Health Organization (WHO).
Carbapenems are a group of vital ‘last-resort’ antibiotics used to treat serious, multi-drug resistant infections when other antibiotics, like penicillin, have failed. But some bacteria have found a way to survive treatment with carbapenems, by producing enzymes called metallo-beta-lactamases (MBLs) that break down the carbapenem antibiotics, stopping them from working.
There is no licensed drug that targets MBLs, and only one in clinical trials – so there is an urgent need to find new drugs that overcome resistance, protect carbapenems and keep these precious medicines working for longer. WHO estimates that by 2050, 10 million deaths will be due annually to antimicrobial resistance, overtaking the number of cancer related deaths – making it one of the most pressing health problems faced by humanity today.
Research conducted by scientists from the Ineos Oxford Institute (IOI) for Antimicrobial Research at the University of Oxford and several institutions across Europe, found that the new class of enzyme blockers, called indole carboxylates, can stop MBL resistance enzymes working leaving the antibiotic free to attack and kill bacteria such as E. coli in the lab and in infections in mice.
The new research, published in Nature Chemistry, was funded by the Innovative Medicines Initiative (IMI) through the European Lead Factory (ELF) and the European Gram-Negative Antibacterial Engine (ENABLE) programs.
The researchers first screened hundreds of thousands of chemicals to see which would attach tightly to MBLs to stop them working, and which didn’t react with any human proteins, leading to the discovery of the indole carboxylates as promising new candidates. Using a process called crystallography to zoom in to take a closer look at how they work, the researchers found these potential drugs attach to MBLs in a completely different way to any other drugs – they imitate the interaction of the antibiotic with the MBLs. This clever Trojan Horse trick allows these potential drugs to be highly effective against a very wide range of MBL-producing superbugs.
The potential new drugs in combination with carbapenems were found to be 5 times more potent at treating severe bacterial infections than carbapenems alone, and at a less concentrated dose. Importantly, these potential drugs show only mild side effects in mice.
