Molecular modelling of SdiA protein by selected flavonoid and terpenes compounds to attenuate virulence in Klebsiella pneumoniae

Abstract

Klebsiella pneumoniae is one of the perturbing multidrug resistant (MDR) and ESKAPE pathogens contributing to the mounting morbidity, mortality and extended rate of hospitalization. Its virulence, often regulated by quorum sensing (QS) reinforces the need to explore alternative and prospective antivirulence agents, relatively from plants secondary metabolites. Computer aided drug discovery using molecular modelling techniques offers advantage to investigate prospective drugs to combat MDR pathogens. Thus, this study employed virtual screening of selected terpenes and flavonoids from medicinal plants to interrupt the QS associated SdiA protein in K. pneumoniae to attenuate its virulence. 4LFU was used as a template to model the structure of SdiA. ProCheck, Verify3D, Ramachandran plot scores, and ProSA-Web all attested to the model's good quality. Since SdiA protein in K. pneumoniae leads to the expression of virulence, 31 prospective bioactive compounds were docked for antagonistic potential. The stability of the protein-ligand complex, atomic motions and inter-atomic interactions were further investigated through molecular dynamics simulations (MDS) at 100 ns production runs. The binding free energy was estimated using the molecular mechanics/poisson-boltzmann surface area (MM/PB-SA). Furthermore, the drug-likeness properties of the studied compounds were validated. Docking studies showed phytol possesses the highest binding affinity (−9.205 kcal/mol) while glycitein had −9.752 kcal/mol highest docking score. The MDS of the protein in complex with the best-docked compounds revealed phytol with the highest binding energy of −44.2625 kcal/mol, a low root-mean-square deviation (RMSD) value of 1.54 Å and rootmean-square fluctuation (RMSF) score of 1.78 Å. Analysis of the drug-likeness properties prediction and bioavailability of these compounds revealed their conformed activity to lipinski's rules with bioavailability scores of 0.55 F. The studied terpenes and flavonoids compounds effectively thwart SdiA protein, therefore regulate inter-or intra cellular communication and associated in virulence Enterobacteriaceae, serving as prospective antivirulence drugs.

Dictyostelium discoideum-assisted pharmacognosy of plant resources for discovering antivirulence molecules targetingKlebsiella pneumoniae

“…For instance, sesquiterpene lactones, such as helenalin and its derivatives, might be responsible for the observed cytotoxicity, as previously reported 18,19 . On the other hand, some flavonoids and terpenes can be accountable for attenuated virulence, as previously reported for Klebsiella pneumoniae 20 .…”

Herbal concoction Unveiled: A computational analysis of phytochemicals' pharmacokinetic and toxicological profiles using novel approach methodologies (NAMs)

“…Understanding these compounds' physicochemical characteristics is crucial for forecasting their bioavailability, toxicity, and possible therapeutic effects. The research offers significant insights into these properties ( Adeosun et al, 2022 ).…”

Extracts of Selected South African Medicinal Plants Mitigate Virulence Factors in Multidrug‐Resistant Strains of Klebsiella pneumoniae

“…K. pneumoniae , a Gram-negative, nonmotile, usually capsulated, facultatively anaerobic bacteria belonging to the family Enterobacteriaceae [ 9 ], is known for its pathogenicity towards humans causing digestive, urinary, and respiratory tract infections [ 10 ]. It has also been reported to be implicated with septicaemia, soft tissue infections, intraabdominal infections, and wound and blood infections [ 11 ]. K. pneumoniae possesses virulence factors such as capsular antigens, adherence factors for biofilm formation, O -lipopolysaccharide, exopolysaccharides, and siderophores linked to its infectivity and virulence [ 12 , 13 ].…”