Enzyme inhibitors offer potential method to fight Listeria

North Carolina State University researchers have identified new compounds that could effectively reduce the virulence of the Listeria bacterium, which has caused 180 deaths in South Africa since last year.

The research, conducted by assistant professor of computational chemistry Denis Fourches, postdoctoral researcher Melaine Kuenemann and professor emeritus of microbiology Paul Omdorff, found that by inhibiting a specific enzyme of Listeria, glucose-1-phosphate uridylyltransferase (GalU), the bacteria cell surface was significantly changed. They concluded that these chemical modifications reduced the virulence of Listeria, making it less deadly.

The team then went about finding potential compounds that could inhibit GalU. Using computer models, they screened over 88,000 compounds and 37 showed potential. Of these, three were considered effective enough to be studied in more depth.

Fourches said in a news release: “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. This is true research at the interface of disciplines.”

The researchers found that inhibiting the enzyme resulted in Listeria being more vulnerable to the antibiotic cefotaxime, with Omdorff saying: “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.”

“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.”

The Listeria crisis in South Africa is still ongoing. The World Health Organisation (WHO) reported that it is the largest Listeria outbreak ever documented, and the origin of the outbreak was traced to two ‘polony’ meat processors. In response, human rights lawyer Richard Spoor said on Monday he planned to file a lawsuit against Tiger Brands, one of the two companies in question. Four deaths have also recently been reported in Australia due to Listeria bacteria in rockmelons.

When asked about the potential of inhibiting the GalU enzyme, Fourches told Food Processing Technology: “This is very unclear at this early stage. Our main concern is to optimise the potency and selectivity for the next generation of GalU inhibitors in order to make sure those molecules only target GalU enzymes when Listeria is exposed to them.”

Concerning a possible treatment for listeriosis, Fourches added: “Also unclear at this point. But one could envision that treating those patients with a mix of antibiotics and GalU inhibitors could potentially boost the efficacy of the treatment. Again, this is very far down the road as our molecules should be seen as drug-like chemical probes, not drug candidates.”