Journal
ACS OMEGA
Volume 5, Issue 18, Pages 10466-10480Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.0c00590
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Funding
- Assistance Publique-Les Hopitaux de Paris (AP-HP)
- University Paris-Sud
- Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LERMIT)
- French National Research Agency [ANR-10-LABX-33]
- Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) DesInMBL [ANR-14-JAMR-002]
- French National Centre for Scientific Research-CNRS
- IR-RMN-THC [Fr3050]
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New Delhi metallo-beta-lactamase-1 (NDM-1) has recently emerged as a global threat because of its ability to confer resistance to all common beta-lactam antibiotics. Understanding the molecular basis of beta-lactam hydrolysis by NDM is crucial for designing NDM inhibitors or beta-lactams resistant to their hydrolysis. In this study, for the first time, NMR was used to study the influence of Zn(II) ions on the dynamic behavior of NDM-1. Our results highlighted that the binding of Zn(II) in the NDM-1 active site induced several structural and dynamic changes on active site loop 2 (ASL2) and L9 loops and on helix a2. We subsequently studied the interaction of several flavonols: morin, quercetin, and myricetin were identified as natural and specific inhibitors of NDM-1. Quercetin conjugates were also synthesized in an attempt to increase the solubility and bioavailability. Our NMR investigations on NDM-1/flavonol interactions highlighted that both Zn(II) ions and the residues of the NDM-1 ASL1, ASL2, and ASL4 loops are involved in the binding of flavonols. This is the first NMR interaction study of NDM-1/inhibitors, and the models generated using HADDOCK will be useful for the rational design of more active inhibitors, directed against NDM-1.
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