A new weapon against rifampin-resistant bacteria

Found in Italian soil, pseudouridimycin kills bacteria through a different mechanism than the antibiotic rifampin.

A Rutgers University-led team has discovered a new antibiotic that killed a range of drug-resistant bacteria in the lab. The drug, produced by a microbe found in Italian soil, could come in handy against bacteria that have developed resistance to the antibiotic rifampin.

Rifampin is primarily used to treat tuberculosis and typically deployed alongside other drugs to treat drug-resistant and multidrug-resistant forms of the disease. It treats other bacterial infections, including Legionnaire’s disease and leprosy.

The new antibiotic, pseudouridimycin, stops bacteria from replicating by blocking the enzyme RNA polymerase, according to a statement. It does this through a different mechanism than rifampin, so rifampin-resistant bacteria are not resistant to pseudouridimycin.

The drug attaches to binding sites on RNA polymerase that are normally used by a nucleoside triphosphate (NTP). This stops NTP from binding onto the enzyme, depriving it of an essential ingredient for RNA synthesis. It has a low rate of resistance because it inhibits a nucleoside. The findings are published in the journal Cell.

"Alterations of the NTP binding site that disrupt binding of the new antibiotic also disrupt RNA polymerase activity, resulting in dead bacteria, rather than resistant bacteria,” said Richard Ebright, a professor of chemistry and chemical biology at the University of Rutgers, in the statement.

In addition to killing a number of types of bacteria in a test tube, pseudouridimycin cured bacterial infections in mice, according to the statement. It is the first drug of its class that targets bacterial RNA polymerase without affecting the human version of the enzyme.

“[It] contains a side-chain that 'reaches' outside the NTP binding site and 'touches' an adjacent site that is present in bacterial RNA polymerase but not in human RNA polymerases and, as a result, it binds more tightly to bacterial RNA polymerase than to human RNA polymerases," Ebright explained.

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While the problem of antibiotic resistance has been a concern for quite some time, no new class of antibiotics has been approved in decades. This is largely because they have the same target as other drugs to which bacteria are becoming resistant, said Grant Pierce of the University of Manitoba. Pierce’s team is working to block a sodium pump that supplies many bacteria with energy.

Another emerging approach is to create an unfamiliar foe for the drug-resistant bugs. Researchers from Rockefeller University developed a hybrid of antibodies and lysins, for example, which attach to carbohydrates presented on bacterial cells and then call forth an immune response to destroy the bacteria.