Ricerc@Sapienza

The alarming increase in antibiotic resistance in opportunistic human pathogens jeopardizes the available therapeutic strategies to control both nosocomial and community-acquired bacterial infections, underlining the need for novel antibacterial drugs with new mechanisms of action. Recently, our group has attempted to repurpose an antimetabolite drug in late preclinical development for anticancer therapy (3-bromopyruvate, 3BP) as an antibacterial compound, inspired by the mechanism of action of 3BP in tumour cells (i.e. inhibition of glycolytic metabolism, which is crucial for the physiology of many bacterial species) and the efficacy and tolerability of this antimetabolite in several animal models. Among eight bacterial species screened, 3BP showed a selective (bactericidal) activity against Staphylococcus aureus, one of the most dreaded opportunistic human pathogens, with effective concentrations in vitro that support its potential use in clinical therapy, especially in the case of pulmonary infection in cystic fibrosis (CF) patients.
The general goal of the present project is to evaluate the antibacterial activity of 3BP against clinical S. aureus isolates, both in vitro and in an animal model of infection, and to decipher the mechanism of action which underlies its efficacy and selectivity towards S. aureus. In particular, in this project we will: (1) confirm the activity of 3BP on a panel of CF and multidrug-resistant (MDR) S. aureus clinical isolates; (2) assess the cytotoxicity of 3BP to human epithelial cells, from both healthy and CF individuals; (3) verify the in vivo efficacy of 3BP against S. aureus using a simple insect model of infection; (4) investigate the synergistic activity of 3BP with antibiotics currently used in the therapy of S. aureus infections; (5) apply a genomics-based approach and genetic validation studies to start characterizing the mechanism of action of 3BP in S. aureus.