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.
Antibiotic resistance is a serious public health concern at the global level. Available antibiotics have saved millions of lives, but are progressively losing their efficacy against many bacterial pathogens. While very few new antibiotics are being developed by the pharmaceutical industry, mainly due to the inherent low reward and high risk of antibiotic research, the rapid spread of antibiotic resistant pathogens both in hospitals and in the community calls for new investments in antibacterial drug discovery. To be effective, these investments should however support innovative experimental approaches able to make the process of antibacterial drug discovery more rapid and economically sustainable.
In this view, the present project aims at investigating the possibility of using a compound already in late preclinical development as anticancer drug to combat infections caused by an important human pathogen, S. aureus, according to a drug discovery strategy, named drug repurposing, which is expected to significantly reduce the time and costs generally associated with standard drug discovery processes.
The experimental programme described in this project will allow, on one hand, to assess the antibacterial activity of the candidate drug (3BP) against different S. aureus strains, both in vitro and in vivo, as well its synergistic activity with currently-available antibiotics and, on the other hand, to decipher the mechanism of action of 3BP in S. aureus cells. Therefore, the information retrieved from the planned research activity will be useful not only to evaluate whether this drug can be effectively repurposed for the therapy of S. aureus infections, but also to identify and characterize a new molecular pathway (the cellular target of 3BP) that could be further investigated in future works for the development of novel anti-S. aureus drugs.