The new class of antibiotic molecules could be used to destroy harmful bacteria that have developed resistance to current antibiotics.
ADEP molecules have an antibiotic activity with a unique mode of action. ADEPs bind to the structure of an enzyme, alter that structure and then deplete the enzyme of its protein supply, thus destroying it. Without a protein supply, the bacteria dies.
Researchers experimented by furthering the natural ability of ADEPs to attack bacteria by altering the ADEP structure to make it more rigid. With increased rigidity, the ADEPS were more successful at binding to the enzyme and, when binding, did so more tenaciously.
Researchers at Brown University and Massachusetts Institute of Technology (MIT) believe that they have increased the naturally occurring biological potency of ADEPs 1, 200 – fold.
The paper outlining the research and findings was published by the Journal of the American Chemical Society.
Dr Sello, professor of chemistry at Brown University, and lead researcher, said:
The work is significant because we have outlined and validated a strategy for the enhancing the potency of this promising class of antibacterial drug leads. The molecules that we have synthesized are among the most potent antibacterial agents ever reported in the literature.”
Professor Sello explained the novel mode of action;
The molecules that we have synthesized are among the most potent antibacterial agents ever reported in the literature. ADEPs kill bacteria by a mechanism by that is distinct from all clinically available anti-bacterial drugs. They work by binding to a protein in bacterial cells that acts as a cellular garbage disposal. This barrel-shaped protein, called ClpP, breaks down proteins that are misfolded or damaged and could be harmful to the cell. However, when ClpP is bound by an 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. For bacteria, a runaway ClpP is deadly.”
ADEPs have been shown in the lab to kill the bacteria in ‘staph’ infections, some forms of pneumonia and tuberculosis among other infections in the lab. The molecules have also been reported to cure bacterial infections in mice and rats.
Since the discovery of the natural antibiotic action of ADEPs, scientists have been making synthetic ADEP analogues to identify compounds that may have the potential to become new drugs.
To test if the more “rigid” ADEPs were more potent in their ability to destroy bacteria, scientists tested the altered ADEPs in a test tube. Results showed that compared with standard ADEPs the modified compounds were more potent against a total of three different dangerous bacteria:
- 32 times more potent against S.aureus
- 600 times more potent against E.faecalis
- 1,200 times more potent against S.pneumoniae
Dr Sello added;
We found that the most potent ADEP analog binds ClpP seven-fold better than the parent compound, yet it has 1,200-fold better antibacterial activity. We believe that some of the increase in potency may stem from the fact that the rigidified ADEPs bind ClpP more tightly and have an enhanced capacity to cross the cell membrane. The improved cell permeability of the ADEP analogs is consistent with reports in the literature that molecules with strong intramolecular hydrogen bonds are particularly good at penetrating cells.”
Press release: http://news.brown.edu/pressreleases/2014/01/adeps