3-D docking pose of potential GalU inhibitor Courtesy North Carolina State University

Researchers from North Carolina State University have pinpointed new compounds that may be effective in containing the virulence of Listeria, a bacterium that can cause severe food poisoning and death.

News of the discovery comes during an ongoing listeriosis outbreak in South Africa that has sickened 1,000 and killed 180. The World Health Organization reports it is the largest outbreak ever documented in the world. It has been traced to processed meat products made with chicken paste and referred to as “polony.”

Listeria bacteria are commonly found in soil. Humans can come into contact with Listeria via contaminated foods or beverages and can develop listeriosis infections, which can lead to severe illness or death — particularly in very young, elderly and/or immunocompromised populations.

Researchers Denis Fourches, assistant professor of computational chemistry; postdoctoral researcher Melaine Kuenemann; and Paul Orndorff, professor emeritus of microbiology, knew that inhibiting a particular enzyme of Listeria — known as glucose-1-phosphate uridylyltransferase (GalU) — led to dramatic modifications of the bacterial cell surface. These chemical modifications in turn rendered Listeria much less virulent and less able to cause illness.

The researchers worked to identify potential compounds that could inhibit the function of GalU. Using computers and cheminformatics methods, they characterized, analyzed and virtually screened more than 88,000 compounds with the potential to inhibit GalU. Computer models found 37 compounds promising enough to be tested in vitro. Of the 37, there were three were deemed effective enough to warrant further study, although many of the other, less active compounds yielded key information about how their chemical structures relate to their activity in inhibiting the enzyme’s function.

“We plan to use our computers to virtually generate thousands of new analogues, virtually screen them, and select another batch of up to 50 molecules to be tested experimentally in the future,” Fourches said in a news release. “This is true research at the interface of disciplines.”

Interestingly, inhibiting GalU also served to make the Listeria more vulnerable to cefotaxime, an antibiotic to which it has a natural resistance.

“While our ultimate objective is to get away from antibiotics altogether, in the near term the antibiotic susceptibility opens up the possibility of combinatorial therapies that could include a GalU inhibitor and a known antibiotic such as cefotaxime,” said Orndorff.

“Ultimately, we believe if the GalU inhibitor is effective enough, the host — human or animal — should be able to eliminate the listerial population without antibiotics. For farmers working toward antibiotic-free farms, this could be a wonderful solution.”

Said Fourches: “This proof-of-concept study shows that small molecules can actually be developed to shut down the activity of one specific bacterial enzyme, leading to the suppression of virulence. This is clearly a new avenue for fighting drug-resistant bacteria.”

A proof-of-concept study uses a certain method or idea in order to demonstrate its feasibility, or a demonstration in principle with the aim of verifying that some concept or theory has practical potential. A proof of concept is usually small and may or may not be complete.