Phytochemicals as Inhibitors of Bacterial Cell Division Protein FtsZ: Coumarins Are Promising Candidates

• Published in: Applied biochemistry and biotechnology Vol. 174; no. 1; pp. 283 - 296
• Main Authors: Duggirala, Sridevi, Nankar, Rakesh P, Rajendran, Selvakumar, Doble, Mukesh
• Format: Journal Article
• Language: English
• Published: Boston Springer-Verlag 01.09.2014; Springer US; Springer; Springer Nature B.V
• Subjects: Animals; antibacterial properties; Bacillus subtilis; Bacillus subtilis - growth & development; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Biochemistry; Biological and medical sciences; Biotechnology; carbon; Cell division; Cell Division - drug effects; Chemistry; Chemistry and Materials Science; coumarin; Cytoskeletal Proteins - antagonists & inhibitors; Cytoskeletal Proteins - chemistry; Cytotoxicity; Drug resistance; E coli; energy; Escherichia coli; Escherichia coli - chemistry; Fundamental and applied biological sciences. Psychology; guanosinetriphosphatase; Humans; kidneys; Mice; NIH 3T3 Cells; Phytochemicals; Polymerization; Proteins; quantitative structure-activity relationships; scopoletin; Scopoletin - chemistry; Scopoletin - pharmacokinetics; screening; Umbelliferones - chemistry; Umbelliferones - pharmacokinetics; Phytochemicals; FtsZ; Protofilaments; Polymerization; T7 loop; Coumarin; GTPase activity
• ISSN: 0273-2289; 1559-0291
• DOI: 10.1007/s12010-014-1056-2

Naturally occurring phytochemicals with reported antibacterial activity were screened for their ability to inhibit the bacterial cell division protein Escherichia coli FtsZ. Among the representative compounds, coumarins inhibit the GTPase and polymerization activities of this protein effectively. Further screening with ten coumarin analogs we identified two promising candidates, scopoletin and daphnetin. The former is found to inhibit the GTPase activity of the protein in a noncompetitive manner. Docking of these coumarins with the modeled protein indicate that they bind to T7 loop, which is different from the GTP-binding site (active site), thereby supporting the experimental data. Lowest binding energy is obtained with scopoletin. 3D QSAR indicates the need for groups such as hydroxyl, diethyl, or dimethyl amino in the 7th carbon for enhanced activity. None of the coumarins exhibited cytotoxicity against NIH/3T3 and human embryonic kidney cell lines. The length of Bacillus subtilis increases in the presence of these compounds probably due to the lack of septum formation. Results of this study indicate the role of coumarins in halting the first step of bacterial cell division process.