Construction and Activity Evaluation of Biphenyl Hydroxamic Acid Dual-Target Antibacterial Inhibitor and Nanocarrier

Gram-negative bacterial infections are characterized by the release of lipopolysaccharide (LPS), a key outer membrane component that triggers a robust host immune response via TLR4 signaling. In this study, three series of dual-target (LpxC/PD-L1) inhibitors were rationally designed via a structural splicing approach, synthesized, and evaluated for their <i>in vitro</i> biological activities. Among them, compound <b>12d</b> displayed potent antibacterial activity and significant dual-target (LpxC/PD-L1) inhibitory efficacy. To improve its bioavailability and targeting capability, the nanocomposite (NC-<b>12d</b>) was further constructed to sense the infection microenvironment. Subsequent <i>in</i> <i>vivo</i> evaluation confirmed the dual therapeutic functions of these agents: effective bacterial suppression and immune activation, which collectively accelerated host recovery from drug-resistant bacterial infection. In summary, this study not only broadens the scope of antibacterial drug development but also offers a drug delivery pathway for the treatment of bacterial infections.