Isoreticular chemistry guided enzymodynamic domino effect for biofilm microenvironment-responsive disinfection
Lunjie Huang, Hongbin Pu, Da‐Wen Sun
Abstract
Nanozyme therapy promises to conquer daunting antibacterial resistance but lacks effectiveness and specificity in targeting the microbial microenvironment. Herein, an isoreticular principle was introduced in nanozyme discovery to directedly evolve a domino biomimetic reaction specific to drug-resistant bacterial biofilm. The isoreticular Ce-UiO-66-X (X = BDC, BDC-CH3, BDC-OH, BDC-NH2, BDC-NO2, ADC, Fum) MOFs exhibited linker-dependent mimicry of hydrolytic apyrase and redox oxidase, and the phosphorous reactants (ATP/ADP/AMP/Pi) produced by the ATP hydrolysis could spontaneously activate redox reaction in Ce-UiO-66-X. Evidenced by the representative Ce-BDC-X (X = –NO2, -H, and –NH2) nanozymes, the unique domino reaction of Ce-UiO-66-X could simultaneously deplete ATP molecules and trigger enhanced generation of superoxide radicals at the specific time window in the initial bacterial adhesion stage of methicillin-resistant Staphylococcus aureus (MRSA) biofilm formation. Due to the synergistic nanocatalytic mechanism, possible nanoscale penetration effect, and good biocompatibility, Ce-UiO-66-NO2 could effectively target and destroy the metabolic microenvironment of MRSA biofilm in vitro and in vivo, reducing the MRSA biofilm viability to as low as 3.64%. This work demonstrates a new prodrug-like enzymodynamic antibacterial therapeutics based on cooperative multienzyme reactivity.