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Structure of New Delhi metallo-?-lactamase 1 (NDM-1).

ABSTRACT: Antibiotic resistance in bacterial pathogens poses a serious threat to human health and the metallo-?-lactamase (MBL) enzymes are responsible for much of this resistance. The recently identified New Delhi MBL 1 (NDM-1) is a novel member of this family that is capable of hydrolysing a wide variety of clinically important antibiotics. Here, the crystal structure of NDM-1 from Klebsiella pneumoniae is reported and its structure and active site are discussed in the context of other recently deposited coordinates of NDM-1.

SUBMITTER: Green VL

PROVIDER: S-EPMC3212353 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Structure of New Delhi metallo-β-lactamase 1 (NDM-1).

Green Victoria L VL Verma Anil A Owens Raymond J RJ Phillips Simon E V SE Carr Stephen B SB

Acta crystallographica. Section F, Structural biology and crystallization communications 20110906 Pt 10

Antibiotic resistance in bacterial pathogens poses a serious threat to human health and the metallo-β-lactamase (MBL) enzymes are responsible for much of this resistance. The recently identified New Delhi MBL 1 (NDM-1) is a novel member of this family that is capable of hydrolysing a wide variety of clinically important antibiotics. Here, the crystal structure of NDM-1 from Klebsiella pneumoniae is reported and its structure and active site are discussed in the context of other recently deposite ...[more]

PMID: 22102018

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Project description:BACKGROUND:New Delhi metallo-?-lactamase (bla NDM), a plasmid-borne carbapenemase gene associated with significant mortality and severely limited treatment options, is of global public health concern as it is found in extremely diverse Gram-negative bacterial strains. This study thus aims to genetically characterize local and global spread of bla NDM. METHODS:To investigate local transmission patterns in the context of a single hospital, whole genome sequencing data of the first 11 bla NDM-positive bacteria isolated in a local hospital were analyzed to: (1) identify and compare bla NDM-positive plasmids; and (2) study the phylogenetic relationship of the bacteria chromosomes. The global analysis was conducted by analyzing 2749 complete plasmid sequences (including 39 bla NDM-positive plasmids) in the NCBI database, where: (1) the plasmids were clustered based on their gene composition similarity; (2) phylogenetic study was conducted for each bla NDM-positive plasmid cluster to infer the phylogenetic relationship within each cluster; (3) gene transposition events introducing bla NDM into different plasmid backbones were identified; and (4) clustering pattern was correlated with the plasmids' incompatibility group and geographical distribution. RESULTS:Analysis of the first 11 bla NDM-positive isolates from a single hospital revealed very low bla NDM-positive plasmid diversity. Local transmission was characterized by clonal spread of a predominant plasmid with 2 sporadic instances of plasmid introduction. In contrast to the low diversity locally, global bla NDM spread involved marked plasmid diversity with no predominant bacterial clone. Thirty-nine (1.4 %) out of the 2749 complete plasmid sequences were bla NDM-positive, and could be resolved into 7 clusters, which were associated with plasmid incompatibility group and geographical distribution. The bla NDM gene module was witnessed to mobilize between different plasmid backbones on at least 6 independent occasions. CONCLUSIONS:Our analysis revealed the complex genetic pathways of bla NDM spread, with global dissemination characterized mainly by transposition of the bla NDM gene cassette into varied plasmids. Early local transmission following plasmid introduction is characterized by plasmid conjugation and bacterial spread. Our findings emphasize the importance of plasmid molecular epidemiology in understanding bla NDM spread.

Project description:BackgroundAntibiotic resistance is a global health crisis. The adage that "prevention is better than cure" is especially true regarding antibiotic resistance because the resistance appears and spreads much faster than the production of new antibiotics. Vaccination is an important strategy to fight infectious agents; however, this strategy has not attracted sufficient attention in antibiotic resistance prevention. New Delhi metallo-beta-lactamase (NDM) confers resistance to many beta-lactamases, including important carbapenems like imipenem. Our goal in this study is to use an immunoinformatics approach to develop a vaccine that can elicit strong and specific immune responses against NDMs that prevent the development of antibiotic-resistant bacteria.ResultsIn this study, 2194 NDM sequences were aligned to obtain a conserved sequence. One continuous B cell epitope and three T cell CD4+ epitopes were selected from NDMs conserved sequence. Epitope conservancy for B cell and HLA-DR, HLA-DQ, and HLA-DP epitopes was 100.00%, 99.82%, 99.41%, and 99.86%, respectively, and population coverage of MHC II epitopes for the world was 99.91%. Permutation of the four epitope fragments resulted in 24 different peptides, of which 6 peptides were selected after toxicity, allergenicity, and antigenicity assessment. After primary vaccine design, only one vaccine sequence with the highest similarity with discontinuous B cell epitope in NDMs was selected. The final vaccine can bind to various Toll-like receptors (TLRs). The prediction implied that the vaccine would be stable with a good half-life. An immune simulation performed by the C-IMMSIM server predicted that two doses of vaccine injection can induce a strong immune response to NDMs. Finally, the GC-Content of the vaccine was designed very similar to E. coli K12.ConclusionsIn this study, immunoinformatics strategies were used to design a vaccine against different NDM variants that could produce an effective immune response against this antibiotic-resistant factor.

Dataset Information

Structure of New Delhi metallo-?-lactamase 1 (NDM-1).

Publications

Structure of New Delhi metallo-β-lactamase 1 (NDM-1).

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