Evolution, Mechanisms, and Therapeutic Implications of Mobile Tetracycline Destructases.

Tetracycline destructases (TDases) pose an emerging global threat by enzymatically inactivating all generations of tetracycline (Tet) antibiotics, including last-resort agents such as tigecycline. Despite their recent identification, TDases have rapidly disseminated worldwide, largely driven by mobile genetic elements and environmental reservoirs. This review synthesizes current knowledge on TDase genomics, structural and catalytic mechanisms, ecological niches, and clinical impacts. We detail the mechanistic distinctions between type 1 and type 2 TDases, emphasizing their divergent structural configurations and substrate specificity profiles. Additionally, we examine strategies for therapeutic intervention, highlighting progress in structure-guided inhibitor development. Key gaps remain in understanding ancestral reservoirs, evolutionary trajectories, and effective surveillance strategies. Addressing these areas through integrative evolutionary, biochemical, and ecological studies is critical for mitigating the clinical spread and therapeutic impact of TDases globally.