Scientists at the University of Oxford have discovered a new potential combination with the power to reverse antimicrobial resistance (AMR) in bacteria that cause sepsis, pneumonia, and UTIs. AMR is a grave issue, and according to recent estimates by WHO, there will be 10 million deaths due to AMR by 2050.
Carbapenems, such as meropenem, are often referred to as ‘last-resort’ antibiotics for serious, multi-drug resistant (MDR) infections. Carbapenems are more stable than other similar antibiotics, and many of the methods bacteria use to resist antibiotics don’t work on carbapenems. However, some bacteria can survive by manufacturing metallo-beta-lactamases (MBLs) that degrade the antibiotic via resistance genes that code for MBLs.
A collaborative project with the Ineos Oxford Institute for Antimicrobial Research and other European researchers found that a new class of enzyme blockers called indole carboxylates can stop MBL resistance enzymes so the antibiotic is now free to kill the intended target bacteria.
By screening hundreds of thousands of chemicals over several years, they found these potential compounds attach to MBLs and imitate the interaction of the antibiotic with the MBLs.
When researchers chemically changed aspects of the compounds and tested them in combination with carbapenems against MDR bacteria in vitro and in vivo in mice subjects, they were found to be 5x more potent than carbapenems alone, and at lower concentrations.
This exciting work with enzyme blockers has the promise and power to fight against AMR and we look forward to seeing the impact of these studies.
References
University of Oxford (2021, Dec 13) New resistance-busting antibiotic combination could extend the use of ‘last-resort’ antibiotics. Link.
Brem, J et al (2021) Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors. Nat. Chem. Link.