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In vivo development of tigecycline resistance in Klebsiella pneumoniae owing to deletion of the ramR ribosomal binding site.

Abstract：

:Tigecycline resistance is emerging among Klebsiella pneumoniae, but knowledge regarding in vivo development of tigecycline resistance is limited. Here we report a new mechanism of tigecycline resistance in K. pneumoniae that evolved during tigecycline therapy. Klebsiella pneumoniae isolates were consecutively obtained from urine samples of a patient with scrotal abscess and urinary tract infection before and during tigecycline treatment. Two tigecycline-resistant K. pneumoniae strains (KP-3R and KP-4R; MIC = 8 µg/mL) were isolated after 41 days and 47 days of tigecycline therapy. These isolates had the same sequence type (ST11) and PFGE patterns as tigecycline-susceptible strains (KP-1S and KP-2S; MIC = 2 µg/mL) initially isolated from the patient. Compared with KP-1S and KP-2S, KP-3R and KP-4R exhibited higher expression of efflux pump AcrAB. Sequence comparison of the repressor gene ramR did not find any mutation within the open-reading frame that exist frequently in tigecycline-resistant K. pneumoniae. Instead, a 12-bp deletion of ramR upstream region including the ribosomal binding site (RBS) TGAGG was observed in KP-3R and KP-4R. qRT-PCR and immunoblotting analyses showed that KP-3R and KP-4R did not have impaired ramR transcription but had abolished RamR protein production. Furthermore, xylE reporter assay demonstrated that KP-3R and KP-4R had a defect in RamR translation caused by the 12-bp deletion. Complementing KP-3R and KP-4R with functional ramR suppressed expression of acrAB and consequently restored tigecycline susceptibility. This is the first report identifying deletion of the ramR RBS as a mechanism of in vivo tigecycline resistance in K. pneumoniae developing during tigecycline therapy.

journal_name

Int J Antimicrob Agents

journal_title

International journal of antimicrobial agents

authors

Ye M,Ding B,Qian H,Xu Q,Jiang J,Huang J,Ou H,Hu F,Wang M

doi

10.1016/j.ijantimicag.2017.04.024

subject

Has Abstract

pub_date

2017-10-01 00:00:00

pages

523-528

issue

eissn

0924-8579

issn

1872-7913

pii

S0924-8579(17)30239-X

journal_volume

pub_type

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In vivo development of tigecycline resistance in Klebsiella pneumoniae owing to deletion of the ramR ribosomal binding site.