Identification and validation of potent inhibitor of Escherichia coli DHFR from MMV pathogen box

Abstract

The present study is conducted to find the solution of rising antimicrobial resistance (AMR) in Escherichia coli which is a pathogen responsible for fatal systemic infections in human and animals. The enzyme dihydrofolate reductase (DHFR) is found in all organisms. In this study DHFR of E. coli (ec-DHFR) and human DHFR (h-DHFR) is targeted by novel chemical entities (NCE) from the Pathogen box of Medicines for Malaria Venture, Switzerland (MMV) using molecular modelling. The in-silico studies were further validated by in-vitro assays. The virtual screening of 400 MMV compounds was conducted using PyRx standard tool followed by manual docking of selected compounds by Autodock vina and Ligplot program. The in-silico studies showed good binding energy and strong hydrogen bond in docking of MMV675968 with ec-DHFR and no hydrogen bond with h-DHFR. This was further validated by the Molecular dynamic studies that revealed high binding free energy in ec-DHFR and in-vitro assays that produced good synergy in combination study of MMV675968 with last line (meropenem) and last resort (colistin) antibiotics. The extensive MD simulation and energetic analysis thus concludes that MMV675968 targets ec-DHFR. The combination studies were conducted with MMV675968 and FDA approved drugs against a panel of multidrug resistant Escherichia coli isolates. The synergistic results obtained in combination studies concluded that in-vitro data is consistent with in-silico data and that MMV675968 is a potential lead for future process of antimicrobial drug development against the multidrug resistance E. coli.

Communicated by Ramaswamy H. Sarma

Keywords:

• Drug designing
• DHFR
• molecular docking
• Escherichia coli
• MMV compounds

Acknowledgements

We thank the Centre for drug design, discovery and development (C4D) of SRM University, Haryana for providing the necessary research facilities and the Government of India, CCS National Institute of Animal Health, Baghpat (U.P.) for their support for this study. We also thank to THSTI, DBT for computational support. The finding and conclusions in this report are those of authors and do not represent the official position of any of the above organization.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

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