Starving the invader: disrupting iron uptake to defeat Staphylococcus aureus

The rapid emergence of antibiotic-resistant Staphylococcus aureus strains underscores its role as a key contributor to the global antimicrobial resistance (AMR) crisis. A key factor in its virulence and persistence during infection is the ability to acquire iron, an essential nutrient restricted by the host’s defence mechanism known as nutritional immunity. To circumvent host-imposed iron limitation, S. aureus employs two sophisticated iron acquisition systems: the iron-regulated surface determinant (Isd) system, which scavenges heme-bound iron directly from host hemoglobin (Hb), and the siderophore-mediated system, which captures iron from host iron-binding proteins via small chelators, primarily staphyloferrin B (SB), only produced by the most invasive, coagulase-positive S. aureus strains. Here, we present two innovative strategies targeting S. aureus iron metabolism with potential therapeutic applications. The first involves a newly-identified compound (C35)1 that selectively binds Hb and inhibits its interaction with the IsdB receptor. Using both wild-type S. aureus and its isogenic in frame-deletion mutant (ΔisdB), C35 was shown to markedly inhibit S. aureus growth by blocking hemophore-mediated iron uptake, an essential pathway for survival during infection. The second approach targets SbnA, a key enzyme in SB biosynthesis. Searching for citrate (i.e., SbnA physiological inhibitor) analogues, the methyl esters of 2-phenylmaleic acid (2-PhMA) and of 2-phenylsuccinic acid (2-PhSA) were found to impair siderophore-dependent iron acquisition in S. aureus, and its subsequent growth under iron starvation2. Together, these dual approaches targeting both heme- and siderophore-mediated iron uptake pathways provide a robust foundation for the development of next-generation antimicrobial agents against S. aureus multidrug-resistant strains.