Antimicrob Agents Chemother. 2015 Mar 16. pii: AAC.04858-14. [Epub ahead of print]
A Novel Gene Amplification Causes Up-regulation of the PatAB ABC Transporter and Fluoroquinolone Resistance in Streptococcus pneumoniae.
Baylay AJ1, Ivens A2, Piddock LJ3.
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Abstract
Over-expression of the ABC transporter genes patA and patB confers efflux-mediated fluoroquinolone resistance in Streptococcus pneumoniae, and is also linked to pneumococcal stress responses. Although up-regulation of patAB has been observed in many laboratory mutants and clinical isolates, regulatory mechanisms controlling expression of these genes are unknown. In this study, we aimed to identify the cause of high-level constitutive over-expression of patAB in M184, a multidrug resistant mutant of S. pneumoniae R6. Using a whole genome transformation and sequencing approach, we identified a novel duplication of a 9.2 kb region of the M184 genome, which included the patAB genes. This duplication did not affect growth and was semi-stable with a low segregation rate. Expression levels of patAB in M184 were much higher than could be fully explained by doubling of gene dosage alone, and inactivation of the first copy of patA had no effect on multidrug resistance. Using a GFP reporter system, increased patAB expression was ascribed to transcriptional read-through from a tRNA gene upstream of the second copy of patAB. This is the first report of a large genomic duplication causing antibiotic resistance in S. pneumoniae, and also of a genomic duplication causing antibiotic resistance by a promoter switching mechanism.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
PMID: 25779578 [PubMed - as supplied by publisher]
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