Xie, J.; Wang, L.; Wang, X.; Yang, X.; Hu, X.; Xu, C.; Meng, Y.; Liu, J.-H.; Li, C.-R.; You, X.-F.; Li, G.

This study investigated how Staphylococcus aureus adapts under pentoxifylline (PTX) therapy through analyzing three phylogenetically related isolates (L1, L2, L3) from a bacteremia patient. Whole genome sequencing revealed L1 contained a 2400-bp insertion disrupting nupC, while L3 harbored mutations in the anti-Shine-Dalgarno sequences of 16S rRNA. Each isolate evolved distinct mechanisms to reduce c-di-AMP levels, accompanied by changes in survival ability and virulence. Molecular analysis demonstrated PTX noncompetitively inhibits GdpP phosphodiesterase, directly modulating cyclic diadenosine monophosphate (c-di-AMP) signaling. Our findings provide novel insights into how non-antibiotic medications shape bacterial adaptation through second messenger modulation, highlighting the complex trade-offs between stress resistance and fitness in clinical settings.