Cheminformatics identification of phenolics as modulators of key penicillin−binding proteins of Escherichia coli towards interventive antibacterial therapy

ABSTRACT

Data implicating the mutation in penicillin-binding protein (PBP) 3 and occasionally PBP5 in the resistance of Escherichia coli to beta−lactams is intriguing. Thus, the identification of an improved class of inhibitors of PBP3 and PBP5 is imperative, and in this study, phenolics due to their promising antibacterial activities were screened using structure−based pharmacophore and molecular docking approaches against PBP3, and the ability of the lead phenolics to modulate PBP3 and PBP5 was studied using molecular dynamics simulation. The results demonstrated various inhibitory capacities of the lead phenolics, with lysidicichin (−41.66 kcal/mol) and silicristin (−31.11 kcal/mol) being the most potent against PBP3, while epicatechin 3-O-(3-O-methylgallate) (−38.97 kcal/mol) and epigallocatechin-4-benzyl thioether (−37.01 kcal/mol) had higher affinities towards PBP5. Overall, epicatechin gallate had the best broad-spectrum of activity, as the compound was able to bind favourably to both targets. Additionally, the thermodynamic information confirmed the stability of the lead phenolics with both targets. Conclusively, while these observations are suggestive of the modulatory role of the lead phenolics on the growth of E. coli, further in vitro and in vivo validation of the activity elicited by the phenolics in this study is imperative, and efforts are underway in this direction.

KEYWORDS:

• Resistance
• penicillin−binding proteins
• phenolics
• molecular dynamics simulation
• molecular docking

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.

Author’s contribution

SS conceptualised, mobilised funds and managed the study. SS and TRM supervised the study. JOA generated and analyzed the data. JOA wrote the manuscript, while KI revised the first draft. All authors read and contributed to the critical review of the manuscript for intellectual content and approved the submission for publication

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary description

Additional data on the pharmacophore classes of the phenolics and the 2D and 3D interactions of the top−ranked phenolics against PBP3 and PBP5 are presented in the supplementary file (Supplementary Tables S1 and S2, Figure S1).

Additional information

Funding

The authors specially acknowledge the financial assistance of the Directorate of Research and Postgraduate Support, Durban University of Technology (DUT), and the South African Medical Research Council (SAMRC) under a Self-Initiated Research Grant as well as the National Research Foundation (NRF) Research Development Grant for Rated Researchers (Grant number 120433) and the Competitive Programme for Rated Researchers Support (SRUG2204193723) to S. Sabiu. The views and opinions expressed are those of the authors and do not necessarily represent the official views of the funders.