A Comparative Study of the Inhibitory Action of Berberine Derivatives on the Recombinant Protein FtsZ of E. coli

Medicinal plants belonging to the genus Berberis may be considered an interesting source of drugs to counteract the problem of antimicrobial multiresistance. The important properties associated with this genus are mainly due to the presence of berberine, an alkaloid with a benzyltetrahydroisoquinoline structure. Berberine is active against both Gram-negative and Gram-positive bacteria, influencing DNA duplication, RNA transcription, protein synthesis, and the integrity of the cell surface structure. Countless studies have shown the enhancement of these beneficial effects following the synthesis of different berberine analogues. Recently, a possible interaction between berberine derivatives and the FtsZ protein was predicted through molecular docking simulations. FtsZ is a highly conserved protein essential for the first step of cell division in bacteria. The importance of FtsZ for the growth of numerous bacterial species and its high conservation make it a perfect candidate for the development of broad-spectrum inhibitors. In this work, we investigate the inhibition mechanisms of the recombinant FtsZ of Escherichia coli by different N-arylmethyl benzodioxolethylamines as berberine simplified analogues appropriately designed to evaluate the effect of structural changes on the interaction with the enzyme. All the compounds determine the inhibition of FtsZ GTPase activity by different mechanisms. The tertiary amine 1c proved to be the best competitive inhibitor, as it causes a remarkable increase in FtsZ K-m (at 40 mu M) and a drastic reduction in its assembly capabilities. Moreover, a fluorescence spectroscopic analysis carried out on 1c demonstrated its strong interaction with FtsZ (K-d = 26.6 nM). The in vitro results were in agreement with docking simulation studies.

Automated summary

Medicinal plants from the genus Berberis, containing berberine alkaloids, show potential as sources of drugs to combat antimicrobial resistance. Berberine is effective against both Gram-negative and Gram-positive bacteria, affecting various cellular processes. Recent studies have explored the interaction between berberine derivatives and the essential bacterial protein FtsZ. In this study, the inhibition mechanisms of different berberine analogues were investigated on the recombinant FtsZ of Escherichia coli. Results showed that these compounds inhibited FtsZ activity through various mechanisms, with the tertiary amine 1c exhibiting the strongest inhibitory effects and interaction with FtsZ.