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Targeting beta-lactamase activity with Oxacyclohexadecan-2-one in carbapenem-resistant uropathogenic E. coli: A

Priyanka Balaji¹, Madhana Priya N^2,3, Emmanuel Bhaskar M⁴

¹Department of Human Genetics, Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India.

|February 18, 2025

Abstract:

Urinary tract infections caused by uropathogenic Escherichia coli (E. coli) are a global health concern, with rising rates and antibiotic resistance demanding novel treatments. Therefore, in this study, we explored the potential of Oxacyclohexadecan-2-one obtained from Moringa oleifera (M. oleifera) seed, as antibacterial agent against three majorly prevalent carbapenemase-producing E. coli proteins, blaNDM-1 (New Delhi metallo-betalactamase-1), blaNDM-5 (New Delhi metallo-betalactamase-5) and blaOXA-48 (Oxacillinase-48) from the strains Ecw3, EC-114 and T20 respectively. The ethanolic extract of M. oleifera seed was subjected to GC-MS, identifying 135 compounds. PyRx virtual screening, identified the top 10 ligands for each protein following the Rule of 5 and ProTox classes V and VI, with Oxacyclohexadecan-2-one (PubChem ID: 235414) showing best binding affinity across all 3 proteins with an optimized dose (LD50) of 5000mg/kg. Hence, molecular docking was carried out for ligand 235414 along with Imipenem, belonging to the same class V toxicity class with an optimized dose (LD50) of 5000mg/kg. Imipenem is a commonly used FDA drug to treat UTIs, which served as the control in the study. Oxacyclohexadecan-2-one showed higher binding affinity for the beta-lactamase proteins with a docking score of -6.45 kcal/mol, -6.05 kcal/mol and -7.34 kcal/mol compared to -3.41 kcal/mol, -3.99 kcal/mol and -6.36 kcal/mol of Imipenem for NDM-1, NDM-5 and OXA-48 respectively. Dynamic Simulation was performed for 100 ns for Oxacyclohexadecan-2-one and Imipenem bound protein complexes to determine the stability, fluctuations, compactness, bond interaction, solvent accessibility area, free energy landscape and the binding free energy. The results of molecular docking and dynamics were promising for the Oxacyclohexadecan-2-one, suggesting its potent inhibitory effect against the beta-lactamase producing proteins.

Insights

Moringa oleifera seed compound Oxacyclohexadecan-2-one shows potent antibacterial activity against carbapenemase-producing E. coli. This natural compound exhibits higher binding affinity than Imipenem, suggesting a promising new treatment for urinary tract infections.

Area of Science:

Microbiology
Pharmacology
Computational Chemistry

Background:

Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (E. coli) are a global health problem.
Rising antibiotic resistance necessitates the development of novel therapeutic strategies.
Carbapenemase-producing E. coli strains, such as those expressing blaNDM-1, blaNDM-5, and blaOXA-48, pose a significant clinical challenge.

Purpose of the Study:

To investigate the antibacterial potential of Oxacyclohexadecan-2-one, a compound derived from Moringa oleifera seed.
To evaluate its efficacy against key carbapenemase-producing E. coli proteins (blaNDM-1, blaNDM-5, blaOXA-48).
To compare its binding affinity and stability with the antibiotic Imipenem using molecular docking and dynamic simulations.

Main Methods:

Ethanolic extract of Moringa oleifera seed was analyzed using Gas Chromatography-Mass Spectrometry (GC-MS).
PyRx virtual screening was employed to identify potential drug candidates based on the Rule of 5 and ProTox criteria.
Molecular docking and 100 ns molecular dynamic simulations were performed for Oxacyclohexadecan-2-one and Imipenem against target proteins.

Main Results:

Oxacyclohexadecan-2-one demonstrated superior binding affinity to blaNDM-1, blaNDM-5, and blaOXA-48 proteins compared to Imipenem.
Docking scores for Oxacyclohexadecan-2-one were -6.45, -6.05, and -7.34 kcal/mol, respectively, outperforming Imipenem's scores (-3.41, -3.99, -6.36 kcal/mol).
Molecular dynamics simulations indicated favorable stability and binding interactions for Oxacyclohexadecan-2-one-protein complexes.

Conclusions:

Oxacyclohexadecan-2-one exhibits significant potential as an antibacterial agent against carbapenemase-producing E. coli.
Its strong binding affinity and stable interactions suggest it could be a promising lead compound for developing new UTI treatments.
Further research is warranted to explore its therapeutic applications and optimize its efficacy.

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