Shape-shifting protein may form the basis of unbeatable, species-specific antibiotics

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Washington, June 21 : Scientists at Fox Chase Cancer Center say that a small molecule, which locks an essential enzyme in an inactive form, may someday provide researchers with insights significant enough for developing a new class of unbeatable, species-specific antibiotics.

Highlighting their suggestions in the journal Chemistry and Biology, the researchers said that they had discovered a small molecule, which they had named morphlock-1, locked the inactive form of a protein called porphobilinogen synthase (PBGS), an enzyme used by nearly all forms of cellular life.

The researchers revealed that the functioning form of PBGS is built from eight identical component parts (octamer configuration), and is essential among nearly all forms of life in the processes that enable cells to use energy.

According to them, the other configuration is made of six parts (hexamer configuration), and serves as a "standby" mode for the protein.

"As the name suggests, morphlock-1 essentially locks the hexamer configuration into place, preventing its protein subunits from reconfiguring into the active assembly. Targeting morpheeins in their inactive assemblies provides an entirely new approach to drug discovery," says Dr. Eileen Jaffe, a Senior Member of Fox Chase who led the study.

Although the researchers used a pea plant-version of PBGS in their study, they still believe that the principle could apply to bacterial versions of PBGS as well.

"Using morphlock-1 as a base, we are seeking to fine tune the molecule so that it blocks just the bacterial version of the PBGS enzyme, " Jaffe says.

"Because PBGS is so crucial for life, the part of the enzyme where chemistry happens is highly conserved through evolution," Jaffe says, meaning that an all-around PBGS-inhibiting drug would harm bacteria, peas and people alike.

The researcher, however, added that the area where the potential drug binds to the hexamer form of the protein had been found to differ among species, depending how far the organisms had evolved from each other.

Jaffe says that when PBGS is in its inactive hexamer form, there is a small cavity on the surface of the assembled complex.

With the help of computer docking techniques, the researchers identified a suite of small molecules predicted to bind to the cavity.

Jaffe and colleagues later tested a selection of such molecules in the lab to determine whether any of them stabilized the pea PBGS in its hexamer assembly.

The researchers observed that one inhibitor in particular, they named morphlock-1, potently drove the formation of the hexamer in pea PBGS, but not in that of humans, fruit flies or the infectious bacteria Pseudomonas aeruginosa or Vibrio cholerae, the latter of which causes cholera.

Based on their observations, the researchers came to the conclusion that morphlock-1 is a potent inhibitor of pea PBGS, but not of the PBGS from the other organisms.

Jaffe insists that this is the first study to make use of alternate morpheein shapes as a potential strategy for drug discovery, in general, particularly for antibiotics.

"Multi-drug resistance drives the need for developing new antibiotics. Since drugs that stabilize the inactive PBGS hexamer need not be chemically similar to each other, it will be difficult for the bacterium to develop complete resistance to a cocktail of such compounds," Jaffe says.

ANI

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