EOS project "CRITICAL"

Deciphering bacterial persistence of individual cells down to atomic level

(acronym CRITICAL)

Urinary tract infections (UTIs) are a worldwide health concern and are mainly caused by uropathogenic Escherichia coli (UPEC). Antibiotic therapy failure and the chronic nature of UTIs can be attributed to a small fraction of transiently non-growing, antibiotic-tolerant cells called persisters. An innovative strategy to cure chronic UTIs would be to induce growth resumption in UPEC persisters, thereby re-sensitizing them to conventional antibiotics. However, our current understanding of persister awakening is far from complete, hampering the development of anti-persister drugs. In the frame of the EOS - The Excellence of Science programme, we have recenty been awarded a research grant aimed at studying and understanding awakening of UPEC persisters in individual cells up to the atomic level. In this project we will identify novel genes and regulatory RNAs involved in awakening. Furthermore, we will characterise persister effectors at unprecedented detail by combining genetic, biochemical and structural approaches. Finally, in view of developing therapeutics to stimulate awakening, we will validate our findings in a collection of clinically relevant strains and a model of intracellular infection. Combined, results from this project will lead to ground-breaking new insights in persister awakening and will pave the way for the development of critically needed anti-persister drugs to effectively clear UTIs.

To reach the goals set out in this project, we have assembled a strong multi-disciplinary consortium with highly complementary expertise. Partners include Jan Michiels (spokesperson-coordinator), Wim Versées (head of the Structural Enzymology team within the VIB-VUB Center for Structural Biology), Steven Ballet (head of the Organic Chemistry Research Group, VUB), Françoise Van Bambeke (PI of the group “Pharmacologie cellulaire et moléculaire”, UCLouvain), Régis Hallez (PI of the group "Unité de Recherche en Biologie des Micro-organismes", UNamur) and Jörg Vogel (Director of the Institute for Molecular Infection Biology, University of Würzburg, and Founding Director of the Helmholtz Institute for RNA-based Infection Research in Würzburg).