Dipiperazine‐Phenyl Derivatives Based on Convergent Molecular Platforms Can Reverse Multidrug Resistance in Gram‐Negative Bacteria by Inhibiting Efflux and Permeabilizing Cell Membranes

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With the global surge of infections caused by multidrug-resistant (MDR) Gram-negative bacteria, there is an urgent need for breakthrough therapeutic approaches. To overcome the intrinsic resistance mechanisms of bacteria, End-alkyl-modified dipiperazine-phenyl derivatives are designed via convergent molecular platforms (CMPs)-guided multi-target directed ligand (MTDL) strategy. These dual-functional compounds not only inhibit the AcrB-TolC efflux pump system but also enhance bacterial membrane permeability and display a distinctive activity profile across a broad concentration range. Through integrated evaluation combining in vitro activity screening and computational ADMET (absorption, distribution, metabolism, excretion, toxicity) profiling, compound C5 is identified as a promising lead candidate. This compound achieved three notable breakthroughs. First, it reduces biofilm formation by 80% at 1/64 minimum inhibitory concentration (MIC) when combined with antibiotics. Second, unlike conventional antibiotic adjuvants that typically display potentiation within a narrow concentration window (1/4 MIC), C5 maintained robust and consistent synergistic activity across a broad range from 1/64 MIC to 1/4 MIC. Third, C5 markedly enhanced the therapeutic efficacy of antibiotics such as minocycline by over 1000-fold in in vivo infection models, without causing detectable acute toxicity or cytotoxicity. The established MTDL-CMPs integrated platform pioneers a novel "pump-membrane dual blockade" therapeutic paradigm against MDR Enterobacteriaceae infections.