Targeting PrfA from Listeria monocytogenes: A computational drug repurposing approach

Abstract

Humans can develop listeriosis by ingestion of foods contaminated with Listeria monocytogenes (L. monocytogenes), an opportunistic gram-positive ubiquitous bacterium. Whilst the non-invasive form of listeriosis may be asymptomatic or cause mild flu-like symptoms, the invasive form of listeriosis is life-threatening and is associated with high hospitalization and fatality rates. Current antibiotic-based therapies are still effective against listeriosis. However, multi-drug resistant L. monocytogenes strains have already been identified, which represents a new risk in the treatment of invasive listeriosis. Therefore, it is increasingly urgent to identify new compounds that do not target the conventional biochemical pathways disrupted by current antibiotics. Positive Regulatory Factor A (PrfA) is a well-studied transcription factor in L. monocytogenes that is responsible for activating a plethora of virulence factors. Targeting virulence factors is a promising strategy that is being considered to combat bacterial infections, hence targeting PrfA is both logical and attractive. In the present computational drug repurposing approach, a complete FDA-approved drugs dataset of more than 700 compounds was virtually screened by docking the drugs against the structure of PrfA. Three of the most promising top-scored FDA drug candidates were then simulated complexed to PrfA. Data from Molecular docking and Molecular Dynamics simulations suggest that Dutasteride binds PrfA, and as a result, may exhibit inhibitory activity against L. monocytogenes. The use of Dutasteride is safe in humans since it has been administered in the treatment of benign prostatic hyperplasia for decades. Its unique chemical scaffold may represent a valuable starting point for the rapid development of disruptive novel listeria-specific drugs that will be soon needed to combat multi-drug resistant L. monocytogenes strains.