The “golden age of antibiotic discovery” began 65 years ago with a simple strategy: Scoop up dirt, grow the soil-dwelling bacteria in the lab, and screen them for useful compounds. Bacteria in the soil compete fiercely for nutrients. To get an advantage, they produce toxins that kill their neighbors. According to Lewis, soil bacteria “fight with each other. We borrow those compounds and use them as medicine.”
Now scientists at the Waksman Institute — named for Selman Waksman, who developed the soil-screening technique — and colleagues have combined the tried-and-true approach with new technologies to discover a new weapon in our molecular arms race against killer pathogens.
A study published Thursday in the journal Cell describes a compound called pseudouridimycin (PUM for short) discovered in Italian soil that could be a game changer in bacterial defense.
Ebright described PUM as the inaugural member of “an entirely new class of antibacterial compounds effective against drug-resistant bacteria.” Lewis, who was not involved with this study, calls PUM’s discovery “very surprising and completely unanticipated.”
Most antibiotics kill bacteria that are happily multiplying in infected patients. But PUM is predicted to also kill dormant bacteria, such as those that persist in slime layers on our desks and door handles. It does this by inhibiting an enzyme that is required for virtually every function in every organism: polymerase. Polymerase transcribes DNA into molecular messages called RNA. RNA serves as instructions for the construction of all our cellular proteins.
Ebright specializes in polymerase. He and his team have been searching for more than a decade for compounds like PUM that disrupt polymerase. In the new study, they show that PUM not only inhibits polymerase, but it does so in a surprising way.
PUM mimics one of the building blocks of RNA. These building blocks fit into polymerase like a lock and key. To evolve resistance, the bacteria would have to change its polymerase just enough to exclude the impostor PUM while still allowing all the right keys to fit. That makes PUM about 10 times less likely to trigger antibiotic resistance than traditional antibiotics.
In the lab, PUM killed 20 species of bacteria. It is primarily effective against strains that cause strep and staph infections, some of which are resistant to multiple antibiotics. PUM also cured mice infected with a strain of bacteria that causes scarlet fever.
Importantly, PUM specifically interacts with polymerase in bacteria and not human polymerase. This is surprising, because the polymerase for bacteria and humans is thought to have a very similar shape.
Compounds that act by impersonating RNA building blocks have been used in the past to treat viruses including HIV and hepatitis C, but scientists didn’t think that was possible for bacteria. Now that we know this approach can also work against bacteria, libraries of polymerase inhibitors that have been used against viruses can be screened as possible antibiotics.
PUM could move to human clinical trials within three years, and to market within a decade. In the meantime, Waksman’s legacy might again spur a whole new wave of antibiotic discovery. Perhaps most important, said Rolf Muller of the Helmholtz Institute for Pharmaceutical Research in an email, the results of this study “show once again that soil bacteria are still one of the best (if not THE best) source for novel antibiotics.”