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Structural insight into the binding mode of cefotaxime and meropenem to TEM-1, SHV-1, KPC-2, and Amp-C type beta-lactamases

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Abstract

Antimicrobial resistance is an emerging threat to public health around the world. The study employs computational and biophysical methods to investigate the properties of cefotaxime and meropenem’s binding to various beta-lactamases like TEM-1, SHV-1, KPC-2, and Amp-C. The enzyme kinetics of purified proteins revealed an increase in Michaelis constant (Km) value in the presence of meropenem and cefotaxime, indicating a decrease in enzyme affinity for nitrocefin. Proteins interact with meropenem/cefotaxime, causing quenching through complex formation. All proteins have one binding site, and binding constant (Kb) values are 104, indicating strong interaction. The study found that meropenem and cefotaxime had high fitness scores for Amp-C, KPC-2,TEM-1 and SHV-1, with binding energy ranging from −7.4 to −7.8, and hydrogen bonds between them. Molecular Dynamic simulation of protein–ligand complexes revealed cefotaxime-binding proteins have slightly lower Root Mean Square Deviation(RMSD) than meropenem-binding proteins, indicating stable association antibiotics with these proteins.

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Acknowledgements

The authors acknowledge the facility and support provided by the Department of Biotechnology, Ministry of science and technology, Government of India.

Funding

Funding:The authors acknowledge funding from the DBT, Government of India, grant no. BT/PR40148/BTIS/137/20/2021, Tata Innovation Fellowship, BT/HRD/TIF/09/04/2021-22 and NNP DBT GRANT: BT/PR40180/BTIS/137/59/2023. NF is also recipient of senior research fellow from mentioned project.

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  1. Antimicrobial Resistance Lab. Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, 202002, India

    Nabeela Farhat, Tasneem Khanam, Saba Noor & Asad U. Khan

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  1. Nabeela Farhat
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NF, performed all experiments and wrote manuscript, TK, performed some of the experiments, SN performed bioinformatic studies AUK, conceived problem and guided the study provided resources and checked first draft of manuscript.

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Correspondence to Asad U. Khan.

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Farhat, N., Khanam, T., Noor, S. et al. Structural insight into the binding mode of cefotaxime and meropenem to TEM-1, SHV-1, KPC-2, and Amp-C type beta-lactamases. Cell Biochem Biophys (2024). https://doi.org/10.1007/s12013-024-01284-y

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