Abstract
A phenotype of Escherichia coli and Klebsiella pneumoniae, resistant to piperacillin/tazobactam (TZP) but susceptible to carbapenems and 3rd generation cephalosporins, has emerged. The resistance mechanism associated with this phenotype has been identified as hyperproduction of the β-lactamase TEM. However, the mechanism of hyperproduction due to gene amplification is not well understood. Here, we report a mechanism of gene amplification due to a translocatable unit (TU) excising from an IS26-flanked pseudo-compound transposon, PTn6762, which harbours blaTEM-1B. The TU re-inserts into the chromosome adjacent to IS26 and forms a tandem array of TUs, which increases the copy number of blaTEM-1B, leading to TEM-1B hyperproduction and TZP resistance. Despite a significant increase in blaTEM-1B copy number, the TZP-resistant isolate does not incur a fitness cost compared to the TZP-susceptible ancestor. This mechanism of amplification of blaTEM-1B is an important consideration when using genomic data to predict susceptibility to TZP.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / pharmacology*
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Anti-Bacterial Agents / therapeutic use
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Chromosomes, Bacterial / genetics
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DNA Transposable Elements / genetics
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DNA, Bacterial / genetics
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Drug Resistance, Multiple, Bacterial / genetics*
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Drug Therapy, Combination / methods
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Escherichia coli / drug effects
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Escherichia coli / genetics*
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Escherichia coli / isolation & purification
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Escherichia coli Infections / drug therapy*
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Escherichia coli Infections / microbiology
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Escherichia coli Proteins / genetics*
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Gene Amplification
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Gene Expression Regulation, Bacterial
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Genome, Bacterial / genetics
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Humans
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Microbial Sensitivity Tests
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Piperacillin / pharmacology
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Piperacillin / therapeutic use
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Polymorphism, Restriction Fragment Length
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RNA, Ribosomal, 16S / genetics
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Tazobactam / pharmacology
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Tazobactam / therapeutic use
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Whole Genome Sequencing
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beta-Lactamases / genetics*
Substances
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Anti-Bacterial Agents
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DNA Transposable Elements
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DNA, Bacterial
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Escherichia coli Proteins
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RNA, Ribosomal, 16S
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beta-Lactamases
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beta-lactamase TEM-1
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Tazobactam
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Piperacillin