Utilizing nanoinducers for precision degradation of bacterial protein to mitigate antibiotic resistance

Antibiotic resistance stands as a formidable global challenge to public health. Herein, we present a bacterial nanoinducer (bacNID) designed for targeted protein degradation in treating bacterial infections. Specifically, bacNID is engineered by grafting targeting peptides of MurD and SspB onto gold nanoparticles (GNPs). MurD plays a pivotal role in peptidoglycan production for cell wall synthesis, while SspB recruits SsrA-tagged proteins for degradation by ClpXP protease. The effectiveness of bacNIDs in targeted MurD degradation via ClpXP is demonstrated across both Gram-positive and Gram-negative bacterial strains. Importantly, prolonged exposure to bacNIDs does not result in the acquisition of resistance in either Staphylococcus aureus (S. aureus) or Salmonella typhimurium (S. typhimurium), even after 25 successive treatment passages. This stands in stark contrast to the rapid emergence of robust resistance observed with norfloxacin, evidenced by a 243-fold reduction in antibacterial activity against S. aureus after just 15 passages, and a 7410-fold decrease in activity against S. typhimurium over 22 passages. Moreover, the antimicrobial potential of bacNIDs is evaluated in vivo using S. aureus-infected nonhealing skin and corneal wounds. In summary, this study unveils a potent nanotechnology-driven strategy for targeted bacterial protein degradation with promising implications for in vivo antimicrobial applications.