Copper ions restore antibacterial activity of tigecycline by regulating photodegradation pathway under light exposure‌.

Photodegradation of tetracyclines is a research hotspot due to deactivation and toxic degradation products. We observed that only tigecycline and minocycline, at working concentrations, exhibit a reduction in antibacterial activity under light exposure. In contrast, other tetracyclines maintain antibacterial activity post-degradation. Here we have successfully identified chalcanthite, from the mineral drug resource library. Cu2+ salts with development potential were confirmed to restore the antibacterial activity of tigecycline under light exposure against all tested bacterial strains (FIC < 0.5) except for P. aeruginosa. Spectroscopic/Chromatographic characterization combined with quantum chemical calculations elucidated the molecular mechanism by which Cu2+ selectively modulates the photolytic degradation pathway of tigecycline and structural determinants (Protect the dimethylamino group on the D-ring). Multi-omics technologies revealed that Cu2+-mediated (non-antibacterial) inhibition of bacterial ferric citrate transporter. Animal infection models demonstrated the therapeutic efficacy of copper gluconate-tigecycline under photic conditions, yielding adjuvants for topical formulations and a scientific foundation for photostable tetracycline-based antibiotics.