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Development of Tigecycline Resistance in Carbapenemase-Producing Klebsiella pneumoniae Sequence Type 147 via AcrAB Overproduction Mediated by Replacement of the ramA Promoter

Authors
 Eun Jeong Yoon  ;  Yena Oh  ;  Seok Hoon Jeong 
Citation
 ANNALS OF LABORATORY MEDICINE, Vol.40(1) : 15-20, 2020-01 
Journal Title
ANNALS OF LABORATORY MEDICINE
ISSN
 2234-3806 
Issue Date
2020-01
Keywords
AcrAB ; Klebsiella pneumoniae ; Resistance ; Tigecycline ; ramA
Abstract
Background: Carbapenem-resistant K. pneumoniae 2297, isolated from a patient treated with tigecycline for pneumonia, developed tigecycline resistance, in contrast to carbapenem-resistant isolate 1215, which was collected four months prior to the 2297 isolate. Mechanisms underlying tigecycline resistance were elucidated for the clinical isolates.

Methods: The tigecycline minimum inhibitory concentration (MIC) was determined using the broth microdilution method, with or without phenylalanine-arginine β-naphthylamide (PABN), and whole-genome sequencing was carried out by single-molecule real-time sequencing. The expression levels of the genes acrA, oqxA, ramA, rarA, and rpoB were determined by reverse-transcription quantitative PCR.

Results: Both isolates presented identical antibiograms, except for tigecycline, which showed an MIC of 0.5 mg/L in 1215 and 2 mg/L in 2297. The addition of PABN to tigecycline-resistant 2297 caused a four-fold decrease in the tigecycline MIC to 0.5 mg/L, although acrA expression (encoding the AcrAB efflux pump) was upregulated by 2.5 fold and ramA expression (encoding the pump activator RamA) was upregulated by 1.4 fold. We identified a 6,096-bp fragment insertion flanking direct TATAT repeats that disrupted the romA gene located upstream of ramA in the chromosome of K. pneumoniae 2297; the insertion led the ramA gene promoter replacement resulting in stronger activation of the gene.

Conclusions: The K. pneumoniae isolate developed tigecycline resistance during tigecycline treatment. It was related to the overexpression of the AcrAB resistance-nodulation-cell division efflux system due to promoter replacement.
Files in This Item:
T202002639.pdf Download
DOI
10.3343/alm.2020.40.1.15
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
Yonsei Authors
Jeong, Seok Hoon(정석훈) ORCID logo https://orcid.org/0000-0001-9290-897X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/178969
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