Synthesis and Bioactivities of New Membrane-Active Agents with Aromatic Linker: High Selectivity and Broad-Spectrum Antibacterial Activity.

The worldwide emergence of microbial resistance to antibiotics constitutes an important and growing public health threat, and novel antibiotics are urgently needed. In this report, a series of symmetrical membrane-active agents linked by an aromatic nucleus were designed and synthesized. Some showed high antibacterial activity against clinical drug-resistant bacterial isolates including methicillin-resistant (MRSA), carbapenemase-producing , and delhi metallo-β-lactamase-1-producing Enterobacteriaceae (NDM-1), as well as drug-sensitive bacteria including , , , and . Lead compound , with good selectivity for (minimum inhibitory concentration [MIC] 0.25 μg/mL) versus mammalian erythrocytes (hemolytic concentration [HC] 1211 μg/mL), had notable properties, including stability in complex mammalian fluids, rapid killing of pathogens, ability to eradicate established biofilms, and little induction of bacterial drug-resistance. In a mouse MRSA infection model, compound exhibited a similar level of efficacy to vancomycin in killing bacteria and suppressing inflammation, demonstrating its therapeutic potential.