Engineering Polyoxomolybdate Wheels for Enhanced Antibacterial Activity: A Structure-Driven Approach

Albeit the development of polyoxometalate (POM)-based antibiotics has spanned more than three decades, the antibacterial potential of Mo-based POMs (POMos) remains largely untapped. Given the prominent structure-dependent bioactivity of POMs, this study focuses on the structural engineering of wheel-shaped POMos in an attempt to boost their antibacterial performance. Adopting a dimethylarsinate-involved synthetic strategy, unprecedented iso- and hetero-POMo wheels constructed by emerging building blocks and assembly routes have been obtained. Of these, the [Mo^V₁₂Mo^VI₁₈O₉₆]^24- (<b>Mo</b>_<b>30</b>) wheel demonstrated a 10-fold greater efficacy against methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) than the conventional Keggin-type [PMo₁₂O₄₀]^3- (<b>PMo</b>_<b>12</b>), with the reduction of MIC from 1000 μg/mL (532.9 μmol/L, <b>PMo</b>_<b>12</b>) to 100 μg/mL (17.7 μmol/L, <b>Mo</b>_<b>30</b>). The significant decrease in biofilm mass from 93% (<b>Mo</b>_<b>30</b>) to 16% (<b>PMo</b>_<b>12</b>) signifies that the larger size and higher electronegativity of <b>Mo</b>_<b>30</b> might intensify the interaction with cell membrane proteins, resulting in membrane disruption and subsequent bacterial death. The established structure-bioactivity relationship for POMo wheels promises to revitalize research efforts toward POM-based antibiotics of the next generation.