Global gene expression profiling and antibiotic susceptibility after repeated exposure to the carbon monoxide-releasing molecule-2 (CORM-2) in multidrug-resistant ESBL-producing uropathogenic Escherichia coli

Charlotte Sahlberg Bang,Katarina Persson,Isak Demirel,Robert Kruse,Ligia M Saraiva

doi:10.1371/journal.pone.0178541

Charlotte Sahlberg Bang, Katarina Persson + Show 3 more

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https://doi.org/10.1371/journal.pone.0178541

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Journal: PLOS ONE	Publication Date: Jun 7, 2017
Citations: 9	License type: CC BY 4.0

Affiliation: Örebro University

Abstract

Treatment of urinary tract infections is today a challenge due to the increasing prevalence of multidrug-resistant ESBL-producing uropathogenic Escherichia coli (UPEC). There is an urgent need for new treatment strategies for multidrug-resistant UPEC and preferably with targets that have low potential for development of resistance. Carbon monoxide-releasing molecules (CORMs) are novel and potent antibacterial agents. The present study examines the transcriptomic targets of CORM-2 in a multidrug-resistant ESBL-producing UPEC isolate in response to a single exposure to CORM-2 and after repeated exposure to CORM-2. The bacterial viability and minimal inhibitory concentration (MIC) were also examined after repeated exposure to CORM-2. Microarray analysis revealed that a wide range of processes were affected by CORM-2, including a general trend of down-regulation in energy metabolism and biosynthesis pathways and up-regulation of the SOS response and DNA repair. Several genes involved in virulence (ibpB), antibiotic resistance (marAB, mdtABC) and biofilm formation (bhsA, yfgF) were up-regulated, while some genes involved in virulence (kpsC, fepCEG, entABE), antibiotic resistance (evgA) and biofilm formation (artIP) were down-regulated. Repeated exposure to CORM-2 did not alter the gene expression patterns, the growth inhibitory response to CORM-2 or the MIC values for CORM-2, cefotaxime, ciprofloxacin and trimethoprim. This study identifies several enriched gene ontologies, modified pathways and single genes that are targeted by CORM-2 in a multidrug-resistant UPEC isolate. Repeated exposure to CORM-2 did not change the gene expression patterns or fold changes and the susceptibility to CORM-2 remained after repeated exposure.

Highlights

One-fifth of all uropathogenic strains of E. coli (UPEC) are resistant to the most commonly used antibiotics [1]
The present study examines the transcriptomic targets of carbon monoxide-releasing molecule-2 (CORM-2) in a multidrug-resistant extended spectrum beta-lactamase (ESBL)-producing UPEC isolate in response to a single exposure to Carbon monoxide-releasing molecules (CORMs)-2 and after repeated exposure to CORM-2
Therapeutic options are limited for extended spectrum beta-lactamase (ESBL)-producing E. coli, where the bacteria have acquired a plasmid with genes that code for the enzyme ESBL

Summary

Introduction

One-fifth of all uropathogenic strains of E. coli (UPEC) are resistant to the most commonly used antibiotics [1]. Therapeutic options are limited for extended spectrum beta-lactamase (ESBL)-producing E. coli, where the bacteria have acquired a plasmid with genes that code for the enzyme ESBL. ESBL-producing E. coli can inactivate most of the beta-lactam antibiotics and cephalosporins and frequently demonstrate co-resistance to other antibiotics, such as aminoglycosides and quinolones [2]. The most significant factor for the development of antimicrobial resistance has been found to be selection pressure caused by antibiotics [3]. Development of resistance may arise after mutations through stable genetic alterations or be an adaptive phenomenon characterised by induced tolerance when the drug is present [5]. Mechanisms of antibiotic resistance include enzymatic modification of the antibiotic, reprogramming or camouflaging the target by mutation and efflux pumps which pump the antibiotic out of the cell [6]

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