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Comparative analysis of sequences flanking tet(W) resistance genes in multiple species of gut bacteria.

ABSTRACT: tet(W) is one of the most abundant tetracycline resistance genes found in bacteria from the mammalian gut and was first identified in the rumen anaerobe Butyrivibrio fibrisolvens 1.230, where it is highly mobile and its transfer is associated with the transposable chromosomal element TnB1230. In order to compare the genetic basis for tet(W) carriage in different bacteria, we studied sequences flanking tet(W) in representatives of seven bacterial genera originating in diverse gut environments. The sequences 657 bp upstream and 43 bp downstream of tet(W) were 96 to 100% similar in all strains examined. A common open reading frame (ORF) was identified downstream of tet(W) in five different bacteria, while another conserved ORF that flanked tet(W) in B. fibrisolvens 1.230 was also present upstream of tet(W) in a human colonic Roseburia isolate and in another rumen B. fibrisolvens isolate. In one species, Bifidobacterium longum (strain F8), a novel transposase was located within the conserved 657-bp region upstream of tet(W) and was flanked by imperfect direct repeats. Additional direct repeats 6 bp long were identified on each end of a chromosomal ORF interrupted by the insertion of the putative transposase and the tet(W) gene. This tet(W) gene was transferable at low frequencies between Bifidobacterium strains. A putative minielement carrying a copy of tet(W) was identified in B. fibrisolvens transconjugants that had acquired the tet(W) gene on TnB1230. Several different mechanisms, including mechanisms involving plasmids and conjugative transposons, appear to be involved in the horizontal transfer of tet(W) genes, but small core regions that may function as minielements are conserved.

SUBMITTER: Kazimierczak KA

PROVIDER: S-EPMC1538676 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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Comparative analysis of sequences flanking tet(W) resistance genes in multiple species of gut bacteria.

Kazimierczak Katarzyna A KA Flint Harry J HJ Scott Karen P KP

Antimicrobial agents and chemotherapy 20060801 8

tet(W) is one of the most abundant tetracycline resistance genes found in bacteria from the mammalian gut and was first identified in the rumen anaerobe Butyrivibrio fibrisolvens 1.230, where it is highly mobile and its transfer is associated with the transposable chromosomal element TnB1230. In order to compare the genetic basis for tet(W) carriage in different bacteria, we studied sequences flanking tet(W) in representatives of seven bacterial genera originating in diverse gut environments. Th ...[more]

PMID: 16870752

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Project description:Antibiotic resistance has caused a serious threat to public health and human safety. Recently, the emergence of novel resistance gene tet(X4) and its variants threatens the clinical utility of tigecycline, one of the last-line antibiotics for multidrug-resistant (MDR) bacterial infections. It is highly promising to develop effective antibiotic adjuvants to restore the clinical efficacy of existing drugs and extend their life spans. Metal compounds, such as silver, have been widely used as potential antimicrobial agents for decades. However, the potentiating effect of metallo-agents on the existing antibiotics is not fully understood. Here, we found that five bismuth drugs, especially bismuth nitrate [Bi(NO3)3], commonly used in clinical treatment of stomach-associated diseases, effectively boost the antibacterial activity of tigecycline against tet(X)-positive bacteria by inhibiting the enzymatic activity of Tet(X) protein. Furthermore, the combination of Bi(NO3)3 and tigecycline prevents the development of higher-level resistance in Tet(X)-expressing Gram-negative bacteria. Using molecular docking and dynamics simulation assays, we revealed that Bi(NO3)3 can competitively bind to the active center of Tet(X4) protein, while the bismuth atom targets the Tet(X4) protein in a noncompetitive manner and changes the structure of the primary binding pocket. These two mechanisms of action both antagonize the enzymatic activity of Tet(X4) resistance protein on tigecycline. Collectively, these findings indicate the high potential of bismuth drugs as novel Tet(X) inhibitors to treat tet(X4)-positive bacteria-associated infections in combination with tigecycline. IMPORTANCE Recently, high-level tigecycline resistance mediated by tet(X4) and its variants represents a serious challenge for global public health. Antibiotic adjuvant strategy that enhances the activity of the existing antibiotics by using nonantibiotic drugs offers a distinct approach to combat the antibiotic resistance crisis. In this study, we found that bismuth drugs involve bismuth nitrate, a compound previously approved for treatment of stomach-associated diseases, remarkably potentiates tigecycline activity against tet(X)-positive bacteria. Mechanistic studies showed that bismuth drugs effectively suppress the enzymatic activity of Tet(X) resistance protein. Specifically, bismuth nitrate targets the active center of Tet(X4) protein, while bismuth binds to the resistance protein in a noncompetitive manner. Our data open up a new horizon for the treatment of infections caused by tet(X)-bearing superbugs.

Dataset Information

Comparative analysis of sequences flanking tet(W) resistance genes in multiple species of gut bacteria.

Publications

Comparative analysis of sequences flanking tet(W) resistance genes in multiple species of gut bacteria.

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