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Inhibitors against New Delhi metallo-betalactamase-1 (NDM-1) and its variants endemic in Indian settings along with the laboratory functional gain mutant of NDM-1

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Abstract

Purpose

The emergence of NDM-1 producing bacteria has become common in both hospital and community settings, but no inhibitor has yet been available for clinical treatment. Hence, demanding the urgent need of NDM-1 inhibitors, we initiated to screen broad spectrum inhibitors against NDM natural variants and laboratory mutant.

Methods

We used docking and molecular dynamics simulations, in silico pharmacokinetic investigations, and density functional theory calculation to characterize molecules. Furthermore, an in vitro study, including MIC, kinetics, and fluorescence study were carried out to confirm the efficacies of the selected compounds.

Results

According to the findings of the computational studies, three compounds were effective against NDM variants. Fourfold reduction in MIC of imipenem and meropenem was observed when combined with inhibitors (D2573, D2148, and D63) against blaNDM-1, blaNDM-4, blaNDM-6, and blaNDM-1Q123A, while twofold reduction in MIC of imipenem and meropenem was observed against blaNDM-5 and blaNDM-7. Similarly in the presence of inhibitors (D2573, D2148, and D63) the efficiency of nitrocefin hydrolysis by NDM-4, NDM-6, and Q123A decreases to much more extent as compared to NDM-5 and NDM-7. These results showed that the efficacy of these broad spectrum inhibitors decreases with increasing resistance of NDM variants.

Conclusion

This is the first time inhibitors were tested against different NDM natural variants which are endemic in Indian settings. Moreover, a functional gain laboratory mutant was also checked for their efficacies. We may propose these molecules for the pre-clinical trial to further translate.

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Funding

DBT, Government of India, grant no. BT/PR40148/BTIS/137/20/2021 and Tata Innovation Fellowship, HRD-16012/6/2020-AFS-DBT to AUK. NF is also recipient of senior research fellow from mentioned project.

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  1. Medical Microbiology Lab, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, 202002, India

    Nabeela Farhat & Asad U. Khan

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  1. Nabeela Farhat
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NF performed all experiments and wrote first draft of manuscript; AUK conceived idea and guided study and approved draft manuscript after editing.

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Correspondence to Asad U. Khan.

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Farhat, N., Khan, A.U. Inhibitors against New Delhi metallo-betalactamase-1 (NDM-1) and its variants endemic in Indian settings along with the laboratory functional gain mutant of NDM-1. Eur J Clin Microbiol Infect Dis (2024). https://doi.org/10.1007/s10096-024-04761-7

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