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Tn5406, a new staphylococcal transposon conferring resistance to streptogramin a and related compounds including dalfopristin.

ABSTRACT: We characterized a new transposon, Tn5406 (5,467 bp), in a clinical isolate of Staphylococcus aureus (BM3327). It carries a variant of vgaA, which encodes a putative ABC protein conferring resistance to streptogramin A but not to mixtures of streptogramins A and B. It also carries three putative genes, the products of which exhibit significant similarities (61 to 73% amino acid identity) to the three transposases of the staphylococcal transposon Tn554. Like Tn554, Tn5406 failed to generate target repeats. In BM3327, the single copy of Tn5406 was inserted into the chromosomal att554 site, which is the preferential insertion site of Tn554. In three other independent S. aureus clinical isolates, Tn5406 was either present as a single plasmid copy (BM3318), as two chromosomal copies (BM3252), or both in the chromosome and on a plasmid (BM3385). The Tn5406-carrying plasmids also contain two other genes, vgaB and vatB. The insertion sites of Tn5406 in BM3252 were studied: one copy was in att554, and one copy was in the additional SCCmec element. Amplification experiments revealed circular forms of Tn5406, indicating that this transposon might be active. To our knowledge, a transposon conferring resistance to streptogramin A and related compounds has not been previously described.

SUBMITTER: Haroche J

PROVIDER: S-EPMC127375 | biostudies-literature | 2002 Aug

REPOSITORIES: biostudies-literature

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Tn5406, a new staphylococcal transposon conferring resistance to streptogramin a and related compounds including dalfopristin.

Haroche Julien J Allignet Jeanine J El Solh Névine N

Antimicrobial agents and chemotherapy 20020801 8

We characterized a new transposon, Tn5406 (5,467 bp), in a clinical isolate of Staphylococcus aureus (BM3327). It carries a variant of vgaA, which encodes a putative ABC protein conferring resistance to streptogramin A but not to mixtures of streptogramins A and B. It also carries three putative genes, the products of which exhibit significant similarities (61 to 73% amino acid identity) to the three transposases of the staphylococcal transposon Tn554. Like Tn554, Tn5406 failed to generate targe ...[more]

PMID: 12121902

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Project description:Background: Vancomycin-intermediate Staphylococcus aureus (VISA) emerges typically in the healthcare-associated methicillin-resistant S. aureus and more rarely in community-acquired S. aureus (CA-MRSA). VISA is a serious concern for public health due to its association with persistent infections, the failure of vancomycin treatment, and poor clinical outcomes. Currently, the burden of VISA is somewhat high, even though vancomycin is the mainstay treatment for severe MRSA infections. The molecular mechanisms of reduced glycopeptide susceptibility in S. aureus are constantly under investigation but have still not yet been fully characterized. Methods: Our goal was to investigate the reduced glycopeptide susceptibility mechanisms emerging in a VISA CA-MRSA versus its vancomycin-susceptible (VSSA) CA-MRSA parents in a hospitalized patient undergoing glycopeptide treatment. Comparative integrated omics, Illumina MiSeq whole-genome sequencing (WGS), RNA-Seq, and bioinformatics were performed. Results: Through a comparison of VISA CA-MRSA vs. its VSSA CA-MRSA parent, mutational and transcriptomic adaptations were found in a pool of genes involved, directly or indirectly, in the biosynthesis of the glycopeptide target conferring or supporting the VISA phenotype, and its cross-resistance with daptomycin. This pool included key genes responsible for the biosynthesis of the peptidoglycan precursors, i.e., D-Ala, the D-Ala-D-Ala dipeptide termini of the pentapeptide, and its incorporation in the nascent pentapeptide, as key targets of the glycopeptide resistance. Furthermore, accessory glycopeptide-target genes involved in the pathways corroborated the key adaptations, and thus, supported the acquisition of the VISA phenotype i.e., transporters, nucleotide metabolism genes, and transcriptional regulators. Finally, transcriptional changes were also found in computationally predicted cis-acting small antisense RNA triggering genes related both to the key or accessory adaptive pathways. Conclusion: Our investigation describes an adaptive resistance pathway acquired under antimicrobial therapy conferring reduced glycopeptide susceptibility in a VISA CA-MRSA due to a comprehensive network of mutational and transcriptional adaptations in genes involved in pathways responsible for the biosynthesis of glycopeptide's target or supporters of the key resistance path.

Project description:Transporters belonging to the chromosomally encoded resistance-nodulation-division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria. However, the cotransfer of large gene clusters encoding RND-type pumps from the chromosome to a plasmid appears infrequent, and no plasmid-mediated RND efflux pump gene cluster has yet been found to confer resistance to tigecycline. Here, we identified a novel RND efflux pump gene cluster, designated tmexCD1-toprJ1, on plasmids from five pandrug-resistant Klebsiella pneumoniae isolates of animal origin. TMexCD1-TOprJ1 increased (by 4- to 32-fold) the MICs of tetracyclines (including tigecycline and eravacycline), quinolones, cephalosporins, and aminoglycosides for K.pneumoniae, Escherichia coli, and Salmonella TMexCD1-TOprJ1 is closely related (64.5% to 77.8% amino acid identity) to the MexCD-OprJ efflux pump encoded on the chromosome of Pseudomonas aeruginosa In an IncFIA plasmid, pHNAH8I, the tmexCD1-toprJ1 gene cluster lies adjacent to two genes encoding site-specific integrases, which may have been responsible for its acquisition. Expression of TMexCD1-TOprJ1 in E. coli resulted in increased tigecycline efflux and in K. pneumoniae negated the efficacy of tigecycline in an in vivo infection model. Expression of TMexCD1-TOprJ1 reduced the growth of E. coli and Salmonella but not K. pneumoniaetmexCD1-toprJ1-positive Enterobacteriaceae isolates were rare in humans (0.08%) but more common in chicken fecal (14.3%) and retail meat (3.4%) samples. Plasmid-borne tmexCD1-toprJ1-like gene clusters were identified in sequences in GenBank from Enterobacteriaceae and Pseudomonas strains from multiple continents. The possibility of further global dissemination of the tmexCD1-toprJ1 gene cluster and its analogues in Enterobacteriaceae via plasmids may be an important consideration for public health planning.IMPORTANCE In an era of increasing concerns about antimicrobial resistance, tigecycline is likely to have a critically important role in the treatment of carbapenem-resistant Enterobacteriaceae, the most problematic pathogens in human clinical settings-especially carbapenem-resistant K.pneumoniae Here, we identified a new plasmid-borne RND-type tigecycline resistance determinant, TMexCD1-TOprJ1, which is widespread among K. pneumoniae isolates from food animals. tmexCD1-toprJ1 appears to have originated from the chromosome of a Pseudomonas species and may have been transferred onto plasmids by adjacent site-specific integrases. Although tmexCD1-toprJ1 still appears to be rare in human clinical isolates, considering the transferability of the tmexCD1-toprJ1 gene cluster and the broad substrate spectrum of TMexCD1-TOprJ1, further dissemination of this mobile tigecycline resistance determinant is possible. Therefore, from a "One Health" perspective, measures are urgently needed to monitor and control its further spread. The current low prevalence in human clinical isolates provides a precious time window to design and implement measures to tackle this.

Dataset Information

Tn5406, a new staphylococcal transposon conferring resistance to streptogramin a and related compounds including dalfopristin.

Publications

Tn5406, a new staphylococcal transposon conferring resistance to streptogramin a and related compounds including dalfopristin.

Similar Datasets

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