The research – published today in Cell Chemical Biology – focused on Listeria monocytogenes which the team from Sweden’s Umeå University screened against a collection of ring-fused 2-pyridone compounds.
The found that some of the ring-fused 2-pyridones could both prevent Listeria infecting cells in vitro and damp down the activity of the virulence regulator PrfA, which controls the bacteria’s pathogenic mechanisms.
Targeting virulence rather than viability has advantages over antibiotics the biggest of which - the researchers say - is that the risk of resistance development in disarmed bacteria is lower, because they no longer depend on resistance against the new drug.
Jörgen Johansson, professor at the laboratory for Molecular Infection Medicine Sweden, told us that the long term goal of the project is to develop a drug that can be used to treat Listeria infection.
“At the moment we have not yet finalized our experiments testing the compounds in animals but our aim is to do that during the next six months.”
But the research has application beyond Listeria infections which, while life threatening in 30% of cases, are relatively rare.
According to Fredrik Almqvist and Elisabeth Sauer-Eriksson from Umeå University’s department of Chemistry – who co-authored the paper - ring-fused 2-pyridones could be used to render other bacterial pathogens non-pathogenic.
Almqvist said: “We now know that this class of compounds constitute a great platform for the development of virulence blocking compounds.
"We have developed methods that allow us to fine-tune the substitution pattern and compound properties in such a way that we can direct these compounds towards several different pathogens.”
This was echoed by Sauer-Eriksson, who added “we showed that Umeå has all the tools and expertise needed to understand and develop new antimicrobial strategies.”
Source: Cell Chemical Biology
“Attenuating Listeria monocytogenes virulence by targeting the regulatory protein PrfA”
James A.D. Good, Christopher Andersson, Sabine Hansen, Jessica Wall, K. Syam Krishnan, Afshan Begum, Christin Grundström, Moritz S. Niemiec, Karolis Vaitkevicius, Erik Chorell, Pernilla Wittung-Stafshede, Uwe H. Sauer, A. Elisabeth Sauer-Eriksson, Fredrik Almqvist, and Jörgen Johansson.