Natural flavonoid morin showed anti-bacterial activity against Vibrio cholera after binding with cell division protein FtsA near ATP binding site

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 8; p. 129931
• Main Authors: Nag, Debasish, Dastidar, Debabrata Ghosh, Chakrabarti, Gopal
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.08.2021
• Subjects: adenosinetriphosphatase; antibacterial properties; antibiotic resistance; antibiotics; ATPase activity; cell division; computer simulation; cytotoxicity; Dissociation constant; epithelium; fibroblasts; flavonoids; fluorescence; FtsA; humans; intestines; lungs; Morin; mutants; polymerization; Polymerization inhibition; Vibrio cholerae; Ni2+- NTA; Morin; Vibrio cholerae; Dissociation constant; PIPES; BSA; ATPase activity; VcFtsZ; IPTG; VcFtsA; FtsA; Polymerization inhibition; ATP
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2021.129931

Increasing antibiotic-resistance in bacterial strains has boosted the need to find new targets for drug delivery. FtsA, a major bacterial divisome protein can be a potent novel drug-target. This study finds, morin (3,5,7,2′,4′-pentahydroxyflavone), a bio-available flavonoid, had anti-bacterial activities against Vibrio cholerae, IC50 (50 μM) and MIC (150 μM). Morin (2 mM) kills ~20% of human lung fibroblast (WI38) and human intestinal epithelial (HIEC-6) cells in 24 h in-vitro. Fluorescence studies showed morin binds to VcFtsA (FtsA of V. cholerae) with a Kd of 4.68 ± 0.4 μM, inhibiting the protein's polymerization by 72 ± 7% at 25 μM concentration. Morin also affected VcFtsA's ATPase activity, recording ~80% reduction at 20 μM concentration. The in-silico binding study indicated binding sites of morin and ATP on VcFtsA had overlapping amino acids. Mant-ATP, a fluorescent ATP-derivative, showed increased fluorescence on binding to VcFtsA in absence of morin, but in its presence, Mant-ATP fluorescence decreased. VcFtsA-S40A mutant protein did not bind to morin. VcFtsA–morin interaction inhibits the polymerization of the protein by affecting its ATPase activity. The destabilized VcFtsA assembly in-turn affected the cell division in V. cholerae, yielding an elongated morphology. Collectively, these findings explore the anti-bacterial effect of morin on V. cholerae cells targeting VcFtsA, encouraging it to become a potent anti-bacterial agent. Low cytotoxicity of morin against human cells (host) is therapeutically advantageous. This study will also help in synthesizing novel derivatives that can target VcFtsA more efficiently. [Display omitted] •Morin, a bioflavonoid, shows antibacterial activities with low cytotoxicity.•Morin targets a major cell division protein, FtsA, in Vibrio cholerae.•Morin binds to FtsA close to ATP binding site affecting the ATPase activity of FtsA and inhibiting its polymerization.•Inhibition of FtsA polymerization affects the cell division of Vibrio cholerae altering its morphology to an elongated one.•Morin could be a potent anti-bacterial agent against Vibrio cholerae.