Doctoral Themes - Proposals

FightListeria: Adressing Listeria infections by finding and developing bacterial-internalization blockers

Supervisors

Gonçalo C. Justino, goncalo.justino@tecnico.ulisboa.pt

Registration Institution

Instituto Superior Técnico (Universidade de Lisboa)

Project description

Listeria monocytogenes is a Gram positive non-sporulating pathogenic bacteria that is one of the most virulent foodborne pathogens – listeriosis is the third cause of deaths from foodborne diseases. L. monocytogenes is also the third-most common cause of meningitis in newborns. Over the years, increasing resistance of L. monocytogenes to antiobitics has been observed to come from horizontal transfer from other bacterial species, and, coupled to the biofilm-producing ability of this strain, has contributed to an increasing incidence of listerioris world-wide.

L. monocytogenes is able to cross the intestinal epithelial, the blood-brain barrier and the fetal-placental barrier by expressing surface proteins called internalins that the bacteria to invade mammalian cells by receptor-mediated pathways. Blocking the interaction of bacterial internalins with mammalian receptors is a fundamental approach to manage Listeria infections.

Within the biological chemistry framework, the outstanding goal of this project is to screen the small organic molecule space for internalin blockers that will be used for the initial stages of drug design.

The work will encompass i) isolating and producing the two known L. monocytogenes internalin proteins, ii) developing mass-spectrometry based methods for protein interaction assessment and ligand-binding evaluation, iii) identifying putative internalin ligands by high-throughput protein-ligand docking, and iv) drug lead optimization. These studies will be accompanied by in vitro assays of prototypical L. monocytogenes cultivars susceptibility and sensitivity to the identified and synthesized drug leads.

Keywords

listeriosis, antibiotic design, chemical biology

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