The Multidrug Resistance IncA/C Transferable Plasmid Encodes a Novel Domain-swapped Dimeric Protein-disulfide Isomerase

Premkumar, Lakshmanane; Kurth, Fabian; Neyer, Simon; Schembri, Mark A.; Martin, Jennifer L.

doi:10.1074/jbc.m113.516898

Cited by 7 publications

(3 citation statements)

References 81 publications

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“…IncA/C-type plasmids are large, broad-host-range plasmids − and are usually associated with other extended-spectrum β-lactamase genes, e.g., bla CMY‑2 , − bla TEM , bla VEB , bla CTX‑M , and bla KPC‑2 . These IncA/C plasmids could disseminate antibiotic resistance genes among clinically relevant bacteria, although their conjugal transfer capacities are variable. − As a consequence, the self-conjugative IncA/C plasmid-borne NDM-1 genes and their emergence in the receiving water highlighted the risk of bla NDM‑1 gene dissemination in the environment.…”

Section: Resultsmentioning

confidence: 99%

Propagation of New Delhi Metallo-β-lactamase Genes (bla_NDM-1) from a Wastewater Treatment Plant to Its Receiving River

Yang

Mao

Zhou

et al. 2016

Environ. Sci. Technol. Lett.

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The emergence and spread of NDM-1 (New Delhi metallo-β-lactamase-1) are of great concern to public health. Our previous study reported the occurrence and persistence of NDM-1 genes in wastewater treatment plants (WWTPs). In this study, the occurrence and fate of NDM-1 genes and host bacteria were investigated in a WWTP discharge-receiving river. A considerable level of NDM-1 genes occurred in the receiving river, whereas no NDM-1 genes were detected upstream of the WWTP. This finding together with the DNA sequencing of NDM-1 genes demonstrated that the river NDM-1 is derived from the WWTP. Opportunistic pathogens, like Shigella sonnei, Enterococcus faecium, and Wautersiella falsenii, were isolated from both the receiving water and the WWTP. This study underscores the need to mitigate the release of NDM-1 from WWTPs and indicates that more attention should to be paid to the propagation of these genes to the receiving environment to alleviate their worldwide dissemination.

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Section: Resultsmentioning

confidence: 99%

Propagation of New Delhi Metallo-β-lactamase Genes (bla_NDM-1) from a Wastewater Treatment Plant to Its Receiving River

Yang

Mao

Zhou

et al. 2016

Environ. Sci. Technol. Lett.

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“…Two structurally related enzymes show similar characteristics: the thiol:disulfide interchange protein DsbA from Bordetella parapertussis (PDB code 3HD5) shows an extended α-helix allowing the enzyme to trimerize. The dimerization of the protein disulfide isomerase DsbP is mediated through exchange of the strand β1 …”

Section: Resultsmentioning

confidence: 99%

Rv2466c Mediates the Activation of TP053 To Kill Replicating and Non-replicating Mycobacterium tuberculosis

et al. 2014

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The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis highlights the need to discover new antitubercular agents. Here we describe the synthesis and characterization of a new series of thienopyrimidine (TP) compounds that kill both replicating and non-replicating M. tuberculosis. The strategy to determine the mechanism of action of these TP derivatives was to generate resistant mutants to the most effective compound TP053 and to isolate the genetic mutation responsible for this phenotype. The only non-synonymous mutation found was a g83c transition in the Rv2466c gene, resulting in the replacement of tryptophan 28 by a serine. The Rv2466c overexpression increased the sensitivity of M. tuberculosis wild-type and resistant mutant strains to TP053, indicating that TP053 is a prodrug activated by Rv2466c. Biochemical studies performed with purified Rv2466c demonstrated that only the reduced form of Rv2466c can activate TP053. The 1.7 Å resolution crystal structure of the reduced form of Rv2466c, a protein whose expression is transcriptionally regulated during the oxidative stress response, revealed a unique homodimer in which a β-strand is swapped between the thioredoxin domains of each subunit. A pronounced groove harboring the unusual active-site motif CPWC might account for the uncommon reactivity profile of the protein. The mutation of Trp28Ser clearly predicts structural defects in the thioredoxin fold, including the destabilization of the dimerization core and the CPWC motif, likely impairing the activity of Rv2466c against TP053. Altogether our experimental data provide insights into the molecular mechanism underlying the anti-mycobacterial activity of TP-based compounds, paving the way for future drug development programmes.

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“…These plasmids cannot simultaneously co-exist in one cell because of the interference of replication ( 28 ). IncA/C-type plasmids have recently become a major environmental concern ( 29 ) because they have a broad host range and are capable of spreading multi-drug resistance via conjugative transfer within bacterial communities ( 20 ). However, the mechanisms used by these plasmids to reside in aquatic environments have not yet been determined despite their frequent detection.…”

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confidence: 99%

Persistence of Multi-Drug Resistance Plasmids in Sterile Water under Very Low Concentrations of Tetracycline

et al. 2015

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The persistence of the multi-drug resistance plasmids pAQU1 and IncFIB was examined in bacterial populations under very low selective pressure. We herein demonstrated that these plasmids stably remained not only in the original host, but also in a transconjugant, even after being in a non-culturable state. In seawater microcosms containing Photobacterium damselae 04Ya311 possessing pAQU1, no significant loss of pAQU1 was observed during a 30-d starvation period. The copy numbers of pAQU1 and IncFIB in E. coli were constant. The results of the present study suggest that these plasmids have the ability to remain among various bacteria under oligotrophic conditions with low antibiotic selection pressure.

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The Multidrug Resistance IncA/C Transferable Plasmid Encodes a Novel Domain-swapped Dimeric Protein-disulfide Isomerase

Cited by 7 publications

References 81 publications

Propagation of New Delhi Metallo-β-lactamase Genes (bla_NDM-1) from a Wastewater Treatment Plant to Its Receiving River

Propagation of New Delhi Metallo-β-lactamase Genes (bla_NDM-1) from a Wastewater Treatment Plant to Its Receiving River

Rv2466c Mediates the Activation of TP053 To Kill Replicating and Non-replicating Mycobacterium tuberculosis

Persistence of Multi-Drug Resistance Plasmids in Sterile Water under Very Low Concentrations of Tetracycline

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The Multidrug Resistance IncA/C Transferable Plasmid Encodes a Novel Domain-swapped Dimeric Protein-disulfide Isomerase

Cited by 7 publications

References 81 publications

Propagation of New Delhi Metallo-β-lactamase Genes (blaNDM-1) from a Wastewater Treatment Plant to Its Receiving River

Propagation of New Delhi Metallo-β-lactamase Genes (blaNDM-1) from a Wastewater Treatment Plant to Its Receiving River

Rv2466c Mediates the Activation of TP053 To Kill Replicating and Non-replicating Mycobacterium tuberculosis

Persistence of Multi-Drug Resistance Plasmids in Sterile Water under Very Low Concentrations of Tetracycline

Contact Info

Product

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Propagation of New Delhi Metallo-β-lactamase Genes (bla_NDM-1) from a Wastewater Treatment Plant to Its Receiving River

Propagation of New Delhi Metallo-β-lactamase Genes (bla_NDM-1) from a Wastewater Treatment Plant to Its Receiving River