Modified Molecule-Protein Combination More Powerful Than Common Antibiotics

Researchers have engineered a molecule that could be more effective against antibiotic-resistant bacteria, according to a study published in the Journal of American Chemical Society.

Jason K. Sello and colleagues from Brown University and the Massachusetts Institute of Technology altered an existing molecule, acyldepsipeptide (ADEP), making it up to 1200 times more potent against dangerous bacteria, according to a news release that accompanied publication of the study.

By increasing the rigidity of ADEP molecules, investigators say they can be successfully attached to a ClpP protein. “ADEP conformation observed in the ADEP-ClpP structure is fortified by trans-annular hydrogen bonding and can be further stabilized by judicious replacement of constituent amino acids within the peptidolactone core structure with more conformationally constrained counterparts,” the authors wrote.

Researchers said that attaching basic ADEPs to a ClpP protein can produce dangerous results, noting that “when ClpP is bound by an (unaltered) ADEP, it’s no longer so selective about the proteins it degrades. In essence, the binding by ADEP causes the garbage disposal to run amok and devour healthy proteins throughout the cell.”

“The experiments showed that the modified ADEPs produced the effect at much lower concentrations, indicating a higher binding efficiency,” according to the news release. “The modified molecules were about 7 times better than the standard ones at binding to ClpP.”

According to the statement, ADEPs have combated harmful bacteria that cause tuberculosis, staph infections and pneumonia. However, the transformed ADEP is even more effective. Researchers say that the new ADEP is “32 times more potent against S. aureus, 600 times more potent against E. faecalis, and 1200 times more potent against S. pneumonia.”

While some bacteria produce ADEPs naturally, researchers are trying to create a drug that captures its effect. “For the last few years, scientists including Sello’s group have been making synthetic ADEP analogs, in the hope of identifying compounds with potential as new drugs,” the statement reported.