Unveiling therapeutic efficacy of extract and multi-targeting phytocompounds from Christella dentata (Forssk.) Brownsey & Jermy against multidrug-resistant Pseudomonas aeruginosa.

Abstract

Christella dentata (Forssk.) Brownsey & Jermy has been commonly used in traditional medicinal practices but its effects on multi-drug-resistant (MDR) bacteria have remained unexplored. We aimed to assess the in vitro antibacterial potential of the ethanol extract of Christella dentata (EECD) against MDR Pseudomonas aeruginosa and to identify potential multi-targeting antibacterial phytocompounds through computer-aided drug design focusing on the LasR and LpxC proteins. PPS, FT-IR and GC-MS were used for profiling of the phytocompounds in EECD. The antimicrobial activity of EECD was assessed using in vitro agar well diffusion, disc diffusion, MIC and MBC. Computer-aided drug design was used to identify multi-targeting leads from GC-MS-annotated phytocompounds. EECD exhibited dose-dependent antibacterial activity and revealed the presence of 51 phytocompounds in GC-MS analysis. Among these, three phytocompounds; (2E,4E)-N-isobutylhexadeca-2,4-dienamide (CID 6442402), bicyclo[4.3.0]nonane, 2,2,6,7-tetramethyl-7-hydroxy- (CID 536446) and 1,4-diethylbenzene (CID 7734) were identified as promising antibacterial phytocompounds as they strongly bonded with LasR and LpxC. Of them, CID 536446 and CID 7734 exhibited multiple targeting abilities with LasR and LpxC. On further screening, both CID 536446 and CID 7734 exhibited favorable drug-able, pharmacokinetics and toxicity properties. Finally, molecular dynamics (MD) simulation proved the binding stability of bicyclo[4.3.0]nonane, 2,2,6,7-tetramethyl-7-hydroxy- and 1,4-diethylbenzene to active pockets of LasR and LpxC. The results of this study offer scientific validation for the traditional use of Christella dentata in bacterial infection-related diseases. It also suggests that bicyclo[4.3.0]nonane, 2,2,6,7-tetramethyl-7-hydroxy- and 1,4-diethylbenzene from Christella dentata might be responsible for the antibacterial activity and could act as phytopharmacological leads for the development of LasR and LpxC inhibitors against MDR P. aeruginosa.