Scientists from Brown University and Massachusetts Institute of Technology have come up with new strategies in order to beat tuberculosis.
Over the past few years, a class of compounds called ADEPs had emerged as a promising new weapon in the fight against drug-resistant bacteria. The compounds work by attaching themselves to a cellular enzyme called ClpP, which bacterial cells use to rid themselves of harmful proteins. With an ADEP attached, ClpP can't function properly, and the bacterial cell dies.
Now, scientists have shown new details of how ADEPs bind to the ClpP complex in the bacterium that causes tuberculosis. The researchers are hopeful that the work could serve as a blueprint for optimizing ADEPs for treatment of tuberculosis.
The researchers mixed two ClpP proteins from Mtb in a test tube. They then added ADEPs as a mimic for ClpX, and a compound called a peptide agonist that mimics a protein to be degraded. As they hoped, the researchers showed that the concoction did indeed yield an active ClpP complex capable of degrading both peptides and proteins.
It confirmed the idea that the ADEPs were able to mimic the ClpX and induce ClpP1, ClpP2, and the agonist to come together to form a hyperactive ClpP complex. They also discovered that novel ADEP analogs, synthesized in Sello's lab and used in the experiments, were better at binding and activating ClpP than those that were previously reported.
The researchers went a step further and used X-ray crystallography to analyze the binding of optimized ADEPs to ClpP from Mtb at atomic resolution. The team was surprised to find that the ADEPs bind only to the ClpP2 proteins in the complex, not to ClpP1. That could be a reason ADEPs aren't as effective against TB, said the researchers.
Jason Sello, co-author of the new study, said that fortunately, the structure provided strategies for designing ADEPs that bind better to ClpP, and they had already generated many new ideas about how the ADEP structure could be rationally modified to improve ClpP binding and thus killing of M. tuberculosis.
The team is hopeful that the detailed picture of ADEPs bound to ClpP would continue to reveal new approaches to fighting TB.
The study is published in the Proceedings of the National Academy of Sciences.