(Nature Research, 2020) Prieto Mariscal, Juana María; Rapún Araiz, Beatriz; Gil Puig, Carmen; Penadés, José R.; Lasa Uzcudun, Íñigo; Latasa Osta, Cristina; Ciencias de la Salud; Osasun Zientziak
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 offpatent
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.
