A tale of two old drugs tetracycline and salicylic acid with new perspectives—Coordination chemistry of their Co(II) and Ni(II) complexes, redox activity of Cu(II) complex, and molecular interactions

• Published in: Journal of inorganic biochemistry 2025-01, Vol.262, p.112757, Article 112757
• Main Authors: Xie, Jinhua, Islam, Shahedul, Wang, Le, Zheng, Xiaojing, Xu, Mengsheng, Su, Xiqi, Huang, Shaohua, Suits, Logan, Yang, Guang, Eswara, Prahathees, Cai, Jianfeng, Ming, Li-June
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Cobalt - chemistry; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Copper - chemistry; Metalloantibiotics; Microecology; Nickel - chemistry; Oxidation; Oxidation-Reduction; Salicylic acid; Salicylic Acid - chemistry; Systems thinking; Tetracycline; Tetracycline - chemistry; Tetracycline - pharmacology
• ISSN: 0162-0134; 1873-3344; 1873-3344
• DOI: 10.1016/j.jinorgbio.2024.112757

Extensive use of the broad-spectrum tetracycline antibiotics (TCs) has resulted their wide spread in the environment and drive new microecological balances, including the infamous antibiotic resistance. TCs require metal ions for their antibiotic activity and resistance via interactions with ribosome and tetracycline repressor TetR, respectively, at specific metal-binding sites. Moreover, the Lewis-acidic metal center(s) in metallo-TCs can interact with Lewis-basic moieties of many bioactive secondary metabolites, which in turn may alter their associated chemical equilibria and biological activities. Thus, it is ultimately important to reveal detailed coordination chemistry of metallo-TC complexes. Herein, we report (a) conclusive specific Co2+, Ni2+, and Cu2+-binding of TC revealed by paramagnetic 1H NMR, showing different conformations of the coordination and different metal-binding sites in solution and solid state, (b) significant metal-mediated activity of Cu-TC toward catechol oxidation with different mechanisms by air and H2O2 (i.e., mono- and di-nuclear pathways, respectively), (c) interactions of metallo-TCs with bioactive salicylic acid and its precursor benzoic acid, and (d) noticeable change of TC antibiotic activity by metal and salicylic acid. The results imply that TCs may play broad and versatile roles in maintaining certain equilibria in microecological environments in addition to their well-established antibiotic activity. We hope the results may foster further exploration of previously unknown metal-mediated activities of metallo-TC complexes and other metalloantibiotics. Tetracycline antibiotics are widely spread in the environment owing to their broad use in health and various industries. The Co2+, Ni2+, and Cu2+ complexes show coordination diversity, metal-mediated interactions with biochemicals, and oxidative activity which may intertwine with (micro)ecological balances. The observations suggest their broad potential roles in the environment. [Display omitted] •Conformational variations of tetracycline upon Co2+ and Ni2+ − binding are concluded.•Interactions of metallotetracycline with phytochemicals are revealed by NMR/kinetics.•Cu-tetracycline exhibits unique mono/di-nuclear mechanisms toward catechol oxidation.•Metallotetracycline-phytochemical interactions may be microecological effectors.•Metallotetracycline may interconnect chemical equilibria with microecological balances.