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

Abstract

β-lactam resistance in bacteria is primarily mediated through the production of β-lactamases. Among the several strategies explored to mitigate the issue of β-lactam resistance, the use of plant secondary metabolites in combination with existing β-lactams seem promising. The present study aims to identify possible β-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 β-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 β-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 β-lactam potentiators. This study highlights the ability of metabolites present in FRAE to act as β-lactamase inhibitors.

Communicated by Ramaswamy H. Sarma

Keywords:

• Antibiotic resistance
• Ficus religiosa
• Ω loop
• drug likeness
• flavonoid

Authorship contribution

Bhani Kongkham: Investigation, Data curation, Data validation, Data analysis, Manuscript preparation and Editing, Ajay Yadav: Data curation, Data validation, Monu Dinesh Ojha: Data curation, Data validation, Duraivadivel P.: Data curation, Data validation, Hariprasad P.*: Conceptualization, Visualization, Supervision, Manuscript review and editing.

Acknowledgement

The authors acknowledge the support of the Director and HPC facility of IIT Delhi for providing research space and facilities. Bhani Kongkham thanks University Grants Commission, India for awarding a Senior Research Fellowship.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.