Inhibiting the two-component system GraXRS with verteporfin to combat Staphylococcus aureus infections

Prieto, J. M., Rapún-Araiz, B., Gil, C., Penadés, J. R. , Lasa, I. and Latasa, C. (2020) Inhibiting the two-component system GraXRS with verteporfin to combat Staphylococcus aureus infections. Scientific Reports, 10, 17939. (doi: 10.1038/s41598-020-74873-5) (PMID:33087792) (PMCID:PMC7577973)

Abstract

Infections caused by Staphylococcus aureus pose a serious and sometimes fatal health issue. With the aim of exploring a novel therapeutic approach, we chose GraXRS, a Two-Component System (TCS) that determines bacterial resilience against host innate immune barriers, as an alternative target to disarm S. aureus. Following a drug repurposing methodology, and taking advantage of a singular staphylococcal strain that lacks the whole TCS machinery but the target one, we screened 1.280 off-patent FDA-approved drug for GraXRS inhibition. Reinforcing the connection between this signaling pathway and redox sensing, we found that antioxidant and redox-active molecules were capable of reducing the expression of the GraXRS regulon. Among all the compounds, verteporfin (VER) was really efficient in enhancing PMN-mediated bacterial killing, while topical administration of such drug in a murine model of surgical wound infection significantly reduced the bacterial load. Experiments relying on the chemical mimicry existing between VER and heme group suggest that redox active residue C227 of GraS participates in the inhibition exerted by this FDA-approved drug. Based on these results, we propose VER as a promising candidate for sensitizing S. aureus that could be helpful to combat persistent or antibiotic-resistant infections.

• Item Type: Articles
• Additional Information: This study was supported by Centre for the Development of Industrial Technology (CDTI), (NEO16RECOMBINA; EXP 00112635/SNEO-20161233) Work in the Laboratory of Microbial Pathogenesis is funded by the Spanish Ministry of Science, Innovation and Universities grant BIO2017-83035-R (AEI/FEDER, EU).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Penades, Prof Jose R
• Authors: Prieto, J. M., Rapún-Araiz, B., Gil, C., Penadés, J. R., Lasa, I., and Latasa, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Scientific Reports 10: 17939
• Publisher Policy: Reproduced under a Creative Commons License