Cheminformatics identification of phenolics as modulators of penicillin-binding protein-3 of Pseudomonas aeruginosa towards interventive antibacterial therapy

Abstract

Antibacterial resistance to β-lactams in microorganisms has been attributed majorly to alterations in penicillin-binding proteins (PBPs) coupled with β-lactams’ inactivation by β-lactamase. Consequently, the identification of a novel class of therapeutics with improved modulatory action on the PBPs is imperative and plant secondary metabolites, including phenolics, have found relevance in this regard. For the first time in this study, the over 10,000 phenolics currently known were computationally evaluated against PBP3 of Pseudomonas aeruginosa, a superbug implicated in several nosocomial infections. In doing this, a library of phenolics with an affinity for PBP3 of P. aeruginosa was screened using structure-activity relationship-based pharmacophore and molecular docking approaches. Subsequent thermodynamic screening of the top five phenolics with higher docking scores, more drug-likeness attributes, and feasible synthetic accessibility was achieved through a 120 ns molecular dynamic (MD) simulation. Four of the top five hits had higher binding free energy than cefotaxime (−18.72 kcal/mol), with catechin-3-rhamside having the highest affinity (−28.99 kcal/mol). All the hits were stable at the active site of the PBP3, with catechin-3-rhamside being the most stable (2.14 Å), and established important interactions with Ser294, implicated in the catalytic activity of PBP3. Also, PBP3 became more compact with less fluctuation of the active site amino acid residues following the binding of the hits. These observations are indicative of the potential of the test compounds as PBP3 inhibitors, with catechin-3-rhamside being the most prominent of the compounds that could be further improved for enhanced druggability against PBP3 in vitro and in vivo.

Communicated by Ramaswamy H. Sarma

Keywords:

• Phenolics
• β-lactam antibiotics
• structure-based pharmacophores
• molecular docking
• molecular dynamic simulation

Acknowledgments

The assistance of the National Research Foundation (NRF- TWAS Doctoral Scholarship, grant number 129950), South Africa, to Mr. J. O. Aribisala is duly and thankfully acknowledged. The Centre for High-Performance Computing (CHPC), South Africa is equally acknowledged for granting access to the computing systems used in this study.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary description

Additional data on the validation of molecular docking of other top-ranked compounds, pharmacokinetics and molecular docking scores for the top 20 hit phenolics and that of the antibiotics used as controls are presented in the supplementary file (Supplementary Tables S1 and S2, Figure S1).

Data availability statement

The data is contained within the article or supplementary material.

Author’s contribution

SS conceptualized and supervised the study. JOA generated and analyzed the data. JOA wrote the manuscript. All authors read and contributed to the critical review of the manuscript for intellectual content and approved the submission for publication.

Additional information

Funding

This work is based on the research supported in part by the National Research Foundation of South Africa (Ref Numbers 120433, and SRUG2204193723). Also, the financial assistance of the Directorate of Research and Postgraduate Support, Durban University of Technology, and the South African Medical Research Council (SA MRC) under a Self-Initiated Research Grant is especially acknowledged.