Phenylpropanoids inhibit protofilament formation of Escherichia coli cell division protein FtsZ

Abstract

The earliest step in cell division in bacteria is the assembly of FtsZ, an essential cell division protein, into a ring at the division site. FtsZ has GTPase activity and can assemble in vitro to form protein filaments. The present work involved the study of eight phenylpropanoids (cinnamic, p-coumaric, caffeic, chlorogenic, ferulic, 3,4-dimethoxycinnamic and 2,4,5-trimethoxycinnamic acids and eugenol) as inhibitors of Escherichia coli FtsZ. Phenylpropanoids make up the majority of our diet and act as antibacterial agents. Polymerization and GTPase inhibition assays showed that chlorogenic and caffeic acids were the most active amongst these (IC 50 of 70 and 106 mM, respectively). Circular dichroism studies indicated that chlorogenic acid perturbed the protein conformation and electron microscopy showed distorted filaments. Bacillus subtilis 168 cells treated with the phenylpropanoids were longer when compared to the control. The highest binding energy was observed between chlorogenic acid and the homology modelled E. coli FtsZ, which was consistent with the experimental results. A strong negative correlation was observed between binding energy and inhibition of the polymerization ability. 3D-Quantitative structureactivity relationship studies using GTPase activity indicated that the presence of more hydrophilic groups around the 39-and 49-carbon increased the activity. The effect of stress-induced formation of cell filamentation has to be understood before confirming the role of phenylpropanoids as FtsZ inhibitors. INTRODUCTIONAntimicrobial resistance is a global concern due to its increased prevalence. The major issues are the reduced susceptibility to currently available antimicrobial agents and shortage of newly approved compounds. A growing number of Gram-positive (Staphylococcus aureus, Streptococcus pneumoniae, etc.) and Gram-negative (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, etc.) pathogens are responsible for infection in both the community and health-care settings (Furtado & Nicolau, 2010). Around 19-60 % of Staphylococcus aureus isolates from ocular infections have been shown to be resistant to macrolides, penicillin and fluoroquinolones (McDonald & Blondeau, 2010). The overall levels of antibiotic resistance can be dramatically decreased by focusing on the overuse of antibiotics, the pharmacokinetic and pharmacodynamic properties of different drug formulations, and use of proper hygiene and protective barriers. There is also a need for the introduction of new antimicrobial agents with novel targets.FtsZ is a bacterial cytoskeleton protein which assembles into a protofilament in a GTP-dependent manner. This forms a dynamic Z-ring at the mid-cell position. A study done in E. coli showed that 12 different proteins congregate at the Z-ring in a sequentially dependent pathway, causing assembly of the septal ring that guides the synthesis of the circumferential septum (Buddelmeijer & Beckwith, 2002;Bernhardt & de Boer, 2003;Romberg & Levin, 2003; Schmidt et al., 2004). The septal r...

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“…Cinnamaldehyde was suggested to inhibit cytokinesis as a mode of action on B. cereus because cells could not separate although septa were present after division (Kwon et al, 2003). It has been established that cinnamaldehyde binds to the FtsZ protein, inhibiting its GTP dependent polymerization and thereby preventing cell division (Domadia et al, 2007; Hemaiswarya et al, 2011). The FtsZ protein is an attractive target for antimicrobial therapies as it is evolutionary distant from eukaryotic tubulin, and the predicted interaction of H2 and H3 of cinnamaldehyde with G295 and V208 of FtsZ, respectively, is conserved among FtsZ proteins from several species (Domadia et al, 2007; Hemaiswarya et al, 2011).…”

“…It has been established that cinnamaldehyde binds to the FtsZ protein, inhibiting its GTP dependent polymerization and thereby preventing cell division (Domadia et al, 2007; Hemaiswarya et al, 2011). The FtsZ protein is an attractive target for antimicrobial therapies as it is evolutionary distant from eukaryotic tubulin, and the predicted interaction of H2 and H3 of cinnamaldehyde with G295 and V208 of FtsZ, respectively, is conserved among FtsZ proteins from several species (Domadia et al, 2007; Hemaiswarya et al, 2011). Other enzymes, e.g., the histidine decarboxylase, is also inhibited by cinnamaldehyde (Wendakoon and Morihiko, 1995).…”

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“…Chlorogenic acid, another phenolic compound, is an important biosynthetic intermediate, for example in lignin biosynthesis. Studies showed that chlorogenic acid displayed antibacterial and antifungal activity against certain microorganisms (Sung and Lee 2010;Hemaiswarya et al 2011;Atanasova-Penichon et al 2012). In ginseng callus cultures, accumulation of phenolic compounds was increased 3-fold within 12 h after 1 % chitosan treatment.…”

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“…According to Kwon et al [100] cinnamaldehyde inhibited cytokinesis in Bacillus cereus by inhibiting the septum formation. It has been established that cinnamaldehyde binds to the FtsZ protein, inhibiting its GTPdependent polymerization and thereby preventing cell division [101]. Besides, enzymes like histidine decarboxylase are also inhibited by cinnamaldehyde [97].…”