Rational design of berberine-based FtsZ inhibitors with broad-spectrum antibacterial activity.
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 µg/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.
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
Ning
N
Sun
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China; Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America.
Fung-Yi
FY
Chan
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China; School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, China.
Yu-Jing
YJ
Lu
Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America.
Marco A C
MA
Neves
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
Hok-Kiu
HK
Lui
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
Yong
Y
Wang
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
Ka-Yan
KY
Chow
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
Kin-Fai
KF
Chan
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
Siu-Cheong
SC
Yan
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
Yun-Chung
YC
Leung
Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America; Molsoft L.L.C, San Diego, California, United States of America.
Ruben
R
Abagyan
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
Tak-Hang
TH
Chan
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
Kwok-Yin
KY
Wong
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D001599:Berberine / Q000737:chemistry* / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000648:ultrastructure; D008826:Microbial Sensitivity Tests; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D001599:Berberine