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. Pharmaceutical copper ion salts modulate the photodegradation process of tigecycline under light conditions, generating photoproducts with antibacterial activity, thereby maintaining the in vitro and in vivo antibacterial efficacy.
Xue et al. (2026) studied this question.