A Dual-Functional Prodrug for Imaging and Eradication of Drug-Resistant Gram-Negative Bacteria.

Gram-negative bacteria are increasingly resistant to antibiotics, making the development of effective antimicrobial agents crucial in combating global health threats. In this context, IspH, a key enzyme in the methylerythritol phosphate (MEP) pathway essential for isoprenoid biosynthesis, represents a promising target to develop antibacterial agents for ablating Gram-negative bacteria. However, the anionic groups commonly present in IspH inhibitors hinder their ability to penetrate bacterial cells, preventing them from exhibiting biological activity. Herein, we report effective bactericidal agents against Gram-negative bacteria, including , , and , as well as fluoroquinolone-resistant strains, designed by conjugating an aggregation-induced emission luminogen (AIEgen) carrier with the IspH inhibitor via an ester bond. Once inside the bacteria, the ester bond is cleaved, releasing AIEgen for imaging and the IspH inhibitor for bacterial eradication. Our findings demonstrate that the administration of TNP-NA significantly improves the survival rate of mice with systemic infection. This work offers insights into the development of bacterial target-based antibacterial agents for combating the growing challenges of antimicrobial resistance.