Histidinol dehydrogenase (HisD): a critical regulator of <i>Staphylococcus aureus</i> virulence and a promising target for antivirulence therapy

The increase in drug-resistant <i>Staphylococcus aureus</i> (MRSA) demands therapies that block virulence without promoting resistance. We identify histidinol dehydrogenase (HisD), a histidine-synthesis enzyme, as a key controller of <i>S. aureus</i> pathogenicity. Disrupting HisD genetically or with pixantrone-a newly identified inhibitor-reduces bacterial toxicity, biofilm formation, and virulence gene activity while improving survival and reducing organ damage in infected mice. Pixantrone's dose-dependent suppression of infection severity and inflammation positions it as a therapeutic candidate. Unlike traditional antibiotics, this strategy disarms bacteria rather than killing them, reducing resistance risks. By uncovering HisD's role in connecting metabolism to virulence through the <i>saeR</i>/S system, we reveal a druggable target for fighting multidrug-resistant infections. This work addresses the urgent need for innovative solutions to the global antibiotic resistance crisis, paving the way for therapies that outsmart evolving superbugs.