ABSTRACT
Increasing incidence of multi-drug resistant bacterial pathogens, especially in clinical settings, has been developed into a grave health situation. The drug resistance problem demands the necessity for alternative unique therapeutic policies. One such tactic is targeting the quorum sensing (QS) controlled virulence and biofilm production. In this study, we evaluated a marine steroid Siphonocholin (Syph-1) isolated from Siphonochalina siphonella against Chromobacterium violaceum (CV) 12472, Pseudomonas aeruginosa (PAO1), Methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii (BAA) for biofilm and pellicle formation inhibition, and anti-QS property. MIC of Syph-1 against MRSA, CV, PAO1 was found as 64 µg/mL and 256 µg/mL against BAA. At selected sub-MICs, Syph-1 significantly (P ≤ 0.05) decreased the production of QS regulated virulence functions of CV12472 (violacein) and PAO1 [elastase, total protease, pyocyanin, chitinase, exopolysaccharides, and swarming motility]. The Syph-1 significantly decreased (p = 0.005) biofilm formation ability of tested bacterial pathogens, at sub-MIC level (PAO1 > MRSA > CV > BAA) and pellicle formation in A. baumannii (at 128 µg/mL). Molecular docking and simulation results indicated that Siph-1 was bound at the active site of BfmR N-terminal domain with high affinity. This study highlights the anti-QS and anti-biofilm activity of Syph-1 against bacterial pathogens reflecting its broad spectrum anti-infective potential.
ABSTRACT
New tailored Cu(II) & Zn(II) metal-based antitumor drug entities were synthesized from substituted benzothiazole oâvanillin Schiff base ligands. The complexes were thoroughly characterized by elemental analysis, spectroscopic studies {IR, 1H & 13C NMR, ESI-MS, EPR} and magnetic susceptibility measurements. The structure activity relationship (SAR) studies of benzothiazole Cu(II) & Zn(II) complexes having molecular formulas [C30H22CuN5O7S2], [C30H20Cl2CuN5O7S2], [C30H20CuF2N5O7S2], [C30H22N4O4S2Zn], [C30H20Cl2N4O4S2Zn], and [C30H20F2N5O7S2Zn], with CTâDNA were performed by employing absorption, emission titrations, and hydrodynamic measurements. The DNA binding affinity was quantified by K b and K sv values which gave higher binding propensity for chloro-substituted Cu(II) [C30H20Cl2CuN5O7S2] complex, suggestive of groove binding mode with subtle partial intercalation. Molecular properties and drug likeness profile were assessed for the ligands and all the Lipinski's rules were found to be obeyed. The antimicrobial potential of ligands and their Cu(II) & Zn(II) complexes were screened against some notably important pathogens viz., E. coli, S. aureus, P. aeruginosa, B. subtilis, and C. albicans. The cytotoxicity of the complexes [C30H20Cl2CuN5O7S2], [C30H20CuF2N5O7S2], [C30H20Cl2N4O4S2Zn], and [C30H20F2N5O7S2Zn] were evaluated against five human cancer cell lines viz., MCFâ7 (breast), MIAâPAâCAâ2 (pancreatic), HeLa (cervix) and HepâG2 (Hepatoma) and A498 (Kidney) by SRB assay which revealed that chloro-substituted [C30H20Cl2CuN5O7S2] complex, exhibited pronounced specific cytotoxicity with GI50 value of 4.8 µg/ml against HeLa cell line. Molecular docking studies were also performed to explore the binding modes and orientation of the complexes in the DNA helix.
