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. 2013 May 13;8(5):e62955.
doi: 10.1371/journal.pone.0062955. Print 2013.

Inhibitor discovery of full-length New Delhi metallo-β-lactamase-1 (NDM-1)

Bingzheng Shen  1 , Yan Yu, Hui Chen, Xin Cao, Xingzhen Lao, Yongliang Fang, Yun Shi, Jiao Chen, Heng Zheng
Affiliations

Inhibitor discovery of full-length New Delhi metallo-β-lactamase-1 (NDM-1)

Bingzheng Shen et al. PLoS One. .

Abstract

New Delhi metallo-β-lactmase-1 (NDM-1) has recently attracted extensive attention for its biological activities to catalyze the hydrolysis of almost all of β-lactam antibiotics. To study the catalytic property of NDM-1, the steady-kinetic parameters of NDM-1 toward several kinds of β-lactam antibiotics have been detected. It could effectively hydrolyze most β-lactams (k cat/K m ratios between 0.03 to 1.28 µmol⁻¹.s⁻¹), except aztreonam. We also found that thiophene-carboxylic acid derivatives could inhibit NDM-1 and have shown synergistic antibacterial activity in combination with meropenem. Flexible docking and quantum mechanics (QM) study revealed electrostatic interactions between the sulfur atom of thiophene-carboxylic acid derivatives and the zinc ion of NDM-1, along with hydrogen bond between inhibitor and His189 of NDM-1. The interaction models proposed here can be used in rational design of NDM-1 inhibitors.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. SDS-PAGE (5 to 12%) gels of NDM-1 purification.
Lane 1, Takara protein molecular weight marker; lane 2, boiled cell fraction of E. coli.BL21(DE3) containing pET30a-NDM-1 before induction; lane 3, boiled cell fraction of E. coli. BL21(DE3) containing pET30a-NDM-1 after a 14 h induction with 0.1 mM IPTG at 18°C; lane 4, crude protein after ultrasonication and centrifugation in supernatant solution; lane 5, crude protein after ultrasonication and centrifugation in precipitation; lane 6, His6 tag-NDM-1 after Ni-NTA affinity chromatography; lane 7, full-length NDM-1 after removing the protease, uncut protein and affinity tag.
Figure 2
Figure 2. Molecular structures and IC50 values of inhibitors against NDM-1.
Effects of inhibitors against full-length NDM-1 activity were mediated by meropenem hydrolysis. The precision of the IC50 determinations was within the range of ±10%.
Figure 3
Figure 3. Structure of ticarcillin.
Figure 4
Figure 4. Binding model between compound 4 and NDM-1 in active site.
NDM-1 and compound 4 is shown as solid ribbon model and a stick model. Water-bridge and two zinc ions are shown as spheres, respectively. Key amino acids, His189, His120, His122, Asp124, Cys208 and His250, in active site are shown as line model.
Figure 5
Figure 5. The accurate partial charge values of two zinc ions, water-bridge and sulfur atom of compound 4.
Water-bridge and two zinc ions are shown as spheres. Compound 4 and key amino acids are shown as stick model and line model, respectively.
See this image and copyright information in PMC

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