Defeat Staphylococcus aureus by targeting iron acquisition systems

Background and Aims To tackle antibiotic resistance and the appearance of multidrug-resistant (MDR) Staphylococcus aureus strains, one interesting approach is interfering with iron uptake and metabolism as possible drug targets. To overcome the host iron withholding defenses and establish an infection, S. aureus secretes two siderophores, namely Staphyloferrin A (SA) and Staphyloferrin B (SB), with the latter being produced only by the most invasive, coagulase-positive strains. The aim of this study was to investigate siderophore-mediated iron uptake in S. aureus, to validate the selection of specific molecules able to block this mechanism. Methods We have determined the best growth conditions to investigate the effect of iron starvation in S. aureus, represented by the Chelex®-treated chemically-defined Tris Minimal Succinate (cTMS) medium, in which high levels of siderophore were produced by S. aureus, thus confirming that iron is perceived as a limiting nutrient in cTMS. Results Siderophore-defective strains, namely ΔsbnA, ΔsfaD and ΔsbnAΔsfaD deletion mutants, unable to produce SB, SA or both, respectively, were successfully generated, and their contribution to S. aureus growth was investigated. Both SA and SB were necessary to support Sa growth under iron-deprived conditions. Interestingly ΔsbnAΔsfaD was unable to grow in synthetic media mimicking biological fluids (i.e., human serum). Within the ERASE project (PRIN2020AE3LTA), the SbnA enzyme, involved in SB biosynthesis, was characterized in vitro and specific inhibitors were identified. Conclusions These inhibitors were found to affect siderophore production in S. aureus, paving the way for the discovery of effective molecules able to interfere with iron acquisition, that might find application as innovative antimicrobials.