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 Staphylococcus aureus (MRSA), carbapenemase-producing Enterobacter aerogenes, and delhi metallo-β-lactamase-1-producing
Enterobacteriaceae (NDM-1), as well as drug-sensitive bacteria including Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Stenotrophomonas
maltophilia. Lead compound 2n, with good selectivity
for S. aureus (minimum inhibitory concentration
[MIC] 0.25 μg/mL) versus mammalian erythrocytes (hemolytic concentration
[HC50] 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 2n exhibited a similar level of efficacy to vancomycin in
killing bacteria and suppressing inflammation, demonstrating its therapeutic
potential.