Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant

Liang, Zhongjie; Li, Lianchun; Wang, Yuanyuan; Chen, Limin; Kong, Xiangqian; Yao, Hong; Lan, Lefu; Zheng, Mingyue; Guang-Yang, Cai; Liu, Hong; Shen, Xu; Luo, Cheng; Li, Keqin Kathy; Chen, Kaixian; Jiang, Hualiang

doi:10.1371/journal.pone.0023606

Cited by 66 publications

(58 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This study showed that the importance of N 233 depends on the antibiotics tested for NDM-1, consistent with earlier findings for IMP-1 (28). The dramatic loss of activity by K 224 A to most of the substrates tested in this study indicated the critical role of this residue in substrate catalysis, agreeing with the previous study showing that this mutation disrupts the hydrolytic activity of NDM-1 to meropenem (31). NDM-1 appeared to recognize its substrates through the coordination of the ␤-lactam carbonyl, Zn1, and N 233 , as well as the coordination of the carboxylate oxygen atom of the substrate by K 224 .…”

Section: Resultssupporting

confidence: 92%

Molecular Mechanisms of Substrate Recognition and Specificity of New Delhi Metallo-β-Lactamase

Chiou

Leung

Chen

2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Carbapenems are one of the last lines of defense for Gram-negative pathogens, such as members of the Enterobacteriaceae. Despite the fact that most carbapenems are resistant to extended-spectrum ␤-lactamase (ESBL), emerging metallo-␤-lactamases (MBLs), including New Delhi metallo-␤-lactamase 1 (NDM-1), that can hydrolyze carbapenems have become prevalent and are frequently associated with the so-called "superbugs," for which treatments are extremely limited. Crystallographic study sheds light on the modes of antibiotic binding to NDM-1, yet the mechanisms governing substrate recognition and specificity are largely unclear. This study provides a connection between crystallographic study and the functional significance of NDM-1, with an emphasis on the substrate specificity and catalysis of various ␤-lactams. L1 loop residues L 59 , V 67 , and W 87 were important for the activity of NDM-1, most likely through maintaining the partial folding of the L1 loop or active site conformation through hydrophobic interaction with the R groups of ␤-lactams or the ␤-lactam ring. Substitution of alanine for L 59 showed greater reduction of MICs to ampicillin and selected cephalosporins, whereas substitutions of alanine for V 67 had more impact on the MICs of carbapenems. K 224 and N 233 on the L3 loop played important roles in the recognition of substrate and contributed to substrate hydrolysis. These data together with the structure comparison of the B1 and B2 subclasses of MBLs revealed that the broad substrate specificity of NDM-1 could be due to the ability of its wide active site cavity to accommodate a wide range of ␤-lactams. This study provides insights into the development of efficient inhibitors for NDM-1 and offers an efficient tactic with which to study the substrate specificities of other ␤-lactamases.

show abstract

Section: Resultssupporting

confidence: 92%

Molecular Mechanisms of Substrate Recognition and Specificity of New Delhi Metallo-β-Lactamase

Chiou

Leung

Chen

2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…5B). The lower affinity of FEZ-1 for meropenem was also simulated in an in silico model by Liang et al (45), which showed no such interactions, except for with the lactam motif. Although the main chain conformation surrounding the C4 carboxylate group differs little between subclass B3 MBLs, the slight difference in the position and orientation of side chains may influence the recognition of ␤-lactams.…”

Section: Resultsmentioning

confidence: 99%

Structural Insights into the Subclass B3 Metallo-β-Lactamase SMB-1 and the Mode of Inhibition by the Common Metallo-β-Lactamase Inhibitor Mercaptoacetate

Wachino

Yamaguchi

Mori

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

A novel subclass B3 metallo-␤-lactamase (MBL), SMB-1, recently identified from a Serratia marcescens clinical isolate, showed a higher hydrolytic activity against a wide range of ␤-lactams than did the other subclass B3 MBLs, i.e., BJP-1 and FEZ-1, from environmental bacteria. To identify the mechanism underlying the differences in substrate specificity among the subclass B3 MBLs, we determined the structure of SMB-1, using 1.6-Å diffraction data. Consequently, we found that SMB-1 reserves a space in the active site to accommodate ␤-lactam, even with a bulky R1 side chain, due to a loss of amino acid residues corresponding to F31 and L226 of BJP-1, which protrude into the active site to prevent ␤-lactam from binding. The protein also possesses a unique amino acid residue, Q157, which probably plays a role in recognition of ␤-lactams via the hydrogen bond interaction, which is missing in BJP-1 and FEZ-1, whose K m values for ␤-lactams are particularly high. In addition, we determined the mercaptoacetate (MCR)-complexed SMB-1 structure and revealed the mode of its inhibition by MCR: the thiolate group bridges to two zinc ions (Zn1 and Zn2). One of the carboxylate oxygen atoms of MCR makes contact with Zn2 and Ser221, and the other makes contact with T223 and a water molecule. Our results demonstrate the possibility that MCR could be a potent inhibitor for subclass B3 MBLs and that the screening technique using MCR as an inhibitor would be effective for detecting subclass B3 MBL producers.

show abstract

“…10 New Delhi metallo-β-lactmase-1 (NDM-1), a B1 subclass enzyme first discovered in 2008, 11 has become a global threat because it confers resistance to almost all β-lactam antibiotics and due to its rapid spread of the plasmid-encoded NDM-1 gene. 12,13 The inhibitors of serine-β-lactamases (classes A, C, and D), such as tazobactam and sulbactam, have been used in combination with penicillins to treat infections with resistant bacteria. Novel effective MβL inhibitors for such combination therapies are urgently needed.…”

mentioning

confidence: 99%

Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors

Zhai

Zhang

Kang

et al. 2016

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

ABSTRACT:The metallo-β-lactamases (MβLs) cleave the β-lactam ring of β-lactam antibiotics, conferring resistance against these drugs to bacteria. Twenty-four triazolylthioacetamides were prepared and evaluated as inhibitors of representatives of the three subclasses of MβLs. All these compounds exhibited specific inhibitory activity against NDM-1 with an IC 50 value range of 0.15−1.90 μM, but no activity against CcrA, ImiS, and L1 at inhibitor concentrations of up to 10 μM. Compounds 4d and 6c are partially mixed inhibitors with K i values of 0.49 and 0.63 μM using cefazolin as the substrate. Structure−activity relationship studies reveal that replacement of hydrogen on the aromatic ring by chlorine, heteroatoms, or alkyl groups can affect bioactivity, while leaving the aromatic ring of the triazolylthiols unmodified maintains the inhibitory potency. Docking studies reveal that the typical potent inhibitors of NDM-1, 4d and 6c, form stable interactions in the active site of NDM-1, with the triazole bridging Zn1 and Zn2, and the amide interacting with Lys 211 (Lys224).

show abstract

Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant

Cited by 66 publications

References 21 publications

Molecular Mechanisms of Substrate Recognition and Specificity of New Delhi Metallo-β-Lactamase

Molecular Mechanisms of Substrate Recognition and Specificity of New Delhi Metallo-β-Lactamase

Structural Insights into the Subclass B3 Metallo-β-Lactamase SMB-1 and the Mode of Inhibition by the Common Metallo-β-Lactamase Inhibitor Mercaptoacetate

Triazolylthioacetamide: A Valid Scaffold for the Development of New Delhi Metallo-β-Lactmase-1 (NDM-1) Inhibitors

Contact Info

Product

Resources

About