Rational Design of Berberine-Based FtsZ Inhibitors with Broad-Spectrum Antibacterial Activity

<div><p>Inhibition of the functional activity of Filamenting temperature-sensitive mutant Z (FtsZ) protein, an essential and highly conserved bacterial cytokinesis protein, is a promising approach for the development of a new class of antibacterial agents. Berberine, a benzylisoquinoline alkaloid widely used in traditional Chinese and native American medicines for its antimicrobial properties, has been recently reported to inhibit FtsZ. Using a combination of <i>in silico</i> structure-based design and <i>in vitro</i> biological assays, 9-phenoxyalkyl berberine derivatives were identified as potent FtsZ inhibitors. Compared to the parent compound berberine, the derivatives showed a significant enhancement of antibacterial activity against clinically relevant bacteria, and an improved potency against the GTPase activity and polymerization of FtsZ. The most potent compound <b>2</b> strongly inhibited the proliferation of Gram-positive bacteria, including methicillin-resistant <i>S. aureus</i> and vancomycin-resistant <i>E. faecium</i>, with MIC values between 2 and 4 µg/mL, and was active against the Gram-negative <i>E. coli</i> and <i>K. pneumoniae</i>, with MIC values of 32 and 64 µg/mL respectively. The compound perturbed the formation of cytokinetic Z-ring in <i>E. coli</i>. Also, the compound interfered with <i>in vitro</i> polymerization of <i>S. aureus</i> FtsZ. Taken together, the chemical modification of berberine with 9-phenoxyalkyl substituent groups greatly improved the antibacterial activity via targeting FtsZ.</p>