Mimic molecule distracts superbugs to help old antibiotics work again

Bacteria are exceptional at evolving, so when antibiotics put them under environmental pressures, the survivors will quickly share their resistance genes with the community, until the drugs become useless. So scientists will move onto other antibiotics, which bacteria will also eventually become resistant to, and the cycle continues.

And in the long run, it seems that we’re losing the arms race. It’s critical that we find other ways to weaken bacteria to extend the use of existing drugs, and that was the goal of the new study, led by researchers at the Ineos Oxford Institute for Antimicrobial Research.

Their focus was on improving a class of antibiotics called carbapenems, which are often considered our “last line of defense” to treat infections that are resistant to other drugs. Some types of bacteria have already broken through this barrier, by producing enzymes called metallo-beta-lactamases (MBLs) that break down the drugs. So the researchers set out to find a drug that could target these MBLs and restore function to carbapenems.

The team started by screening hundreds of thousands of different chemicals to find some that might interfere with MBLs, while ideally leaving human proteins alone. They singled out a group called indole carboxylates, and on closer inspection, found that they mimic the binding sites of carbapenems. The MBLs will interact with these molecules instead of the drug, leaving the latter to get to work killing the bacteria.

After optimizing the indole carboxylates, the team tested them against carbapenem-resistant E. coli strains in lab dishes and in mice. They paired the new drug with an existing carbapenem called meropenem, and found that the combination was five times more powerful against the superbugs than the antibiotics alone, and worked at a lower dose. Only mild side effects were seen in the mice.