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.
['Chu|Wenchao|W|', 'Yang|Yi|Y|', 'Cai|Jianfeng|J|0000-0003-3106-3306', 'Kong|Hongtao|H|', 'Bai|Mengmeng|M|', 'Fu|Xiangjing|X|', 'Qin|Shangshang|S|', 'Zhang|En|E|0000-0002-4818-756X']
D000818:Animals D000900:Anti-Bacterial Agents D001419:Bacteria D018441:Biofilms D004195:Disease Models, Animal D024881:Drug Resistance, Bacterial D021902:Enterobacter aerogenes D004755:Enterobacteriaceae D013293:Enterococcus faecalis D004926:Escherichia coli D006367:HeLa Cells D006801:Humans D055624:Methicillin-Resistant Staphylococcus aureus D051379:Mice D008826:Microbial Sensitivity Tests D015394:Molecular Structure D013203:Staphylococcal Infections D020615:Stenotrophomonas maltophilia
membrane-active agents selectivity broad-spectrum antibacterial activity antibiotics low toxicity structure−activity relationships