Molecular docking, dynamics simulation and pharmacokinetic studies of Cyperus articulatus essential oil metabolites as inhibitors of Staphylococcus aureus.

Cyperus articulatus has been extensively studied for its essential oil (EO), active components and antibacterial activities against a wide range of bacteria such as Bacillus megaterium, Streptococcus pyogenes, Staphylococcus epidermidis, Escherichia coli and Staphylococcus aureus. However, knowledge of the biomolecular interaction of the individual EO metabolites responsible for its inhibition activities is lacking. The multi-drug-resistant bacteria S. aureus, which is of prime concern, has been reported to be inhibited by Cyperus articulatus rhizome EO. The present work analyzed the molecular interactions of the major Cyperus articulatus rhizome EO metabolites with the target enzyme TyrRS of S. aureus and studied the conformational dynamics and stability of the protein-ligand complexes. Molecular docking studies of selected EO metabolites such as mustakone, longifolenaldehyde, cyperotundone, α-copaene, ß-calacorene, α-calacorene and khusinol were conducted along with standard drug chloramphenicol for comparative analysis of their binding affinity with S. aureus TyrRS. The metabolites khusinol, mustakone, ß-calacorene and α-calacorene generated comparable docking scores (-6.4, -6.2, -6.1 and -6.2 kcal/mol, respectively) with that of the drug chloramphenicol (-6.3 kcal/mol). Most EO metabolites did not exhibit H-bonding with the S. aureus TyrRS residues and were stabilized through pi-interactions. The MD simulation study illustrated that compounds like mustakone could effectively bind to the receptors of S. aureus TyrRS with high stability and integrity. Pharmacokinetic, drug-like properties and toxicity analysis of the EO metabolites supported the candidature of mustakone and khusinol as pharmacologically important antibacterial drug ingredients. The study envisaged the structural framework of the EO metabolites for antibacterial drug design.Communicated by Ramaswamy H. Sarma.

In vitro and computational studies of the ß-lactamase inhibition and ß-lactam potentiating properties of plant secondary metabolites.

ß-lactam resistance in bacteria is primarily mediated through the production of ß-lactamases. Among the several strategies explored to mitigate the issue of ß-lactam resistance, the use of plant secondary metabolites in combination with existing ß-lactams seem promising. The present study aims to identify possible ß-lactam potentiating plant secondary metabolites following in vitro and in silico approaches. Among 180 extracts from selected 30 medicinal plants, acetone extract of Ficus religiosa (FRAE) bark recorded the least IC50 value of 3.9 mg/ml. Under in vitro conditions, FRAE potentiated the activity of ampicillin, which was evidenced by the significant reduction in IC50 values of ampicillin against multidrug resistant bacteria. Metabolic profiling following HR-LCMS analysis revealed the presence of diverse metabolites viz. flavonoids, alkaloids, terpenoids, etc. in FRAE. Further, ensemble docking of the FRAE metabolites against four Class A ß-lactamase (SHV1, TEM1, KPC2 and CTX-M-27) showed quercetin, taxifolin, myricetin, luteolin, and miquelianin as potential inhibitors with the least average binding energy. In molecular dynamic simulation studies, myricetin formed the most stable complex with SHV1 and KPC-2 while miquelianin with TEM1 and CTX-M-27. Further, all five metabolites interacted with amino acid residue Glu166 in Ω loop of ß-lactamase, interfering with the deacylation step, thereby disrupting the enzyme activity. The pharmacokinetics and ADMET profile indicate their drug-likeness and non-toxic nature, making them ideal ß-lactam potentiators. This study highlights the ability of metabolites present in FRAE to act as ß-lactamase inhibitors.Communicated by Ramaswamy H. Sarma.

Opportunities and challenges in managing antibiotic resistance in bacteria using plant secondary metabolites.

Development of antibiotic resistance (ABR) in bacteria and its multidimensional spread is an emerging global threat that needs immediate attention. Extensive antibiotics (AB) usage results in development of ABR in bacteria by target modification, production of AB degrading enzymes, porin modifications, efflux pumps overexpression, etc. To counter this, apart from strict regulation of AB use and behavioural changes, research and development (R&D) of newer antimicrobials are in place. One such emerging approach to combat ABR is the use of structurally and functionally diverse plant secondary metabolites (PSMs) in combination with the conventional AB. Either the PSMs are themselves antimicrobial or they potentiate the activity of the AB through a range of mechanisms. However, their use is lagging due to poor knowledge of mode of action, structure-activity relationships, pharmacokinetics, etc. This review paper discussed the opportunities and challenges in managing ABR using PSMs. Mechanisms of ABR development in bacteria and current strategies to counter them were studied and the areas where PSMs can play an important role were highlighted. The use of PSMs, both as an anti-resistance and anti-virulence agent in combination therapy to counter multi-drug resistance along with their mechanisms of action, has been discussed in detail. The difficulties in the commercialisation of PSMs and strategies to overcome them along with future priority areas of research have also been given. Following the given R&D path will definitely help in better understanding and utilising the full potential of PSMs in solving the problem of antimicrobial resistance (AMR).