Rational design of berberine-based FtsZ inhibitors with broad-spectrum antibacterial activity

Ning Sun, Fung Yi Chan, Yu Jing Lu, Marco A.C. Neves, Hok Kiu Lui, Yong Wang, Ka Yan Chow, Kin Fai Chan, Siu Cheong Yan, Yun Chung Leung, Ruben Abagyan, Tak Hang Chan, Kwok Yin Wong

Research output: Journal article publicationJournal articleAcademic researchpeer-review

69 Citations (Scopus)

Abstract

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 in silico structure-based design and in vitro 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 2 strongly inhibited the proliferation of Gram-positive bacteria, including methicillin-resistant S. aureus and vancomycin-resistant E. faecium, with MIC values between 2 and 4 μg/mL, and was active against the Gram-negative E. coli and K. pneumoniae, with MIC values of 32 and 64 mg/mL respectively. The compound perturbed the formation of cytokinetic Z-ring in E. coli. Also, the compound interfered with in vitro polymerization of S. aureus FtsZ. Taken together, the chemical modification of berberine with 9-phenoxyalkyl substituent groups greatly improved the antibacterial activity via targeting FtsZ.
Original languageEnglish
Article numbere97514
JournalPLoS ONE
Volume9
Issue number5
DOIs
Publication statusPublished - 13 May 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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