A new study led by New York University researchers found that an FDA-approved hepatitis C drug can increase bacterial sensitivity to antibiotics and decrease antibiotic resistance.
In bacteria, the drug telaprevir works by inhibiting the action of chaperones, which are crucial proteins that fold other proteins in the cell.
“Telaprevir is the first previously clinically approved compound that has been shown to inhibit chaperone function in bacteria,” says Tania Lupoli – the study’s senior author.
“Our research marks a vital step in developing small molecule chaperone inhibitors that can be used in bacteria to increase the power of antibiotics and slow down the evolution of antibiotic resistance.”
From single-cell bacteria to humans, chaperones can be found in practically every cell of every organism. Chaperones are the targets of ongoing drug discovery research because of their crucial function in protein folding—and what occurs when proteins misfold, which can lead to cell toxicity—but researchers have struggled to find small molecule that can selectively target or bind to chaperones.
The goal of this work was to find tiny compounds that could switch off the action of chaperones in bacteria that cause disease. They searched nearly 25,000 compounds, including 1,300 licensed drugs, for small molecules that inhibit chaperones in Mycobacterium TB, the germ that causes tuberculosis.
They discovered telaprevir, an antiviral drug licensed by the FDA for the treatment of hepatitis C. They demonstrated that telaprevir binds to mycobacterial chaperones and inhibits their ability to fold proteins in a series of lab studies using model mycobacteria. This made the mycobacteria more susceptible to drugs, including streptomycin, a routinely used tuberculosis treatment.
Chaperones can also fix the proteins in the cell that induce antibiotic resistance, so blocking chaperone activity with telaprevir reduced mycobacteria susceptibility to the first-line tuberculosis treatment rifampicin. Antibiotic resistance reduction is a key public health goal in the United States and around the world, since an increasing variety of illnesses, including tuberculosis, become more difficult to treat as antibiotics become less effective.
“In the future, we envision that small molecule chaperone inhibitors could be used in combination with antibiotics to enhance antibiotic potency and lower resistance,” says the study author.
While the researchers were extremely happy to discover telaprevir as a chaperone inhibitor, they are still investigating hundreds of telaprevir analogs—compounds with similar molecular structures—to see if others bind more tightly to chaperones, which is essential for moving the research into animal or clinical studies. Future research will also look into how to adapt chaperone inhibitors to just inhibit specific chaperones, such as blocking chaperones in bacteria but not human cells.
“Our work contributes to a small but growing list of small molecules that block the function of chaperones and provides a promising avenue for ongoing study of the role that telaprevir and its analogs can play when administered with antibiotics,” concludes Lupoli.
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