Dataset Information

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.

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.

SUBMITTER: Sahlberg Bang C

PROVIDER: S-EPMC5462378 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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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.

Sahlberg Bang Charlotte C Demirel Isak I Kruse Robert R Persson Katarina K

PloS one 20170607 6

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- ...[more]

PMID: 28591134

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Project description:Cerebral ischemia and neurodegenerative diseases lead to impairment or death of neurons in the central nervous system. Stem cell based therapies are promising strategies currently under investigation. Carbon monoxide (CO) is an endogenous product of heme degradation by heme oxygenase (HO) activity. Administration of CO at low concentrations produces several beneficial effects in distinct tissues, namely anti-apoptotic and anti-inflammatory. Herein the CO role on modulation of neuronal differentiation was assessed. Three different models with increasing complexity were used: human neuroblastoma SH-S5Y5 cell line, human teratocarcinoma NT2 cell line and organotypic hippocampal slice cultures (OHSC). Cell lines were differentiated into post-mitotic neurons by treatment with retinoic acid (RA) supplemented with CO-releasing molecule A1 (CORM-A1). CORM-A1 positively modulated neuronal differentiation, since it increased final neuronal production and enhanced the expression of specific neuronal genes: Nestin, Tuj1 and MAP2. Furthermore, during neuronal differentiation process, there was an increase in proliferative cell number (ki67 mRNA expressing cells) and a decrease in cell death (lower propidium iodide (PI) uptake, limitation of caspase-3 activation and higher Bcl-2 expressing cells). CO supplementation did not increase the expression of RA receptors. In the case of SH-S5Y5 model, small amounts of reactive oxygen species (ROS) generation emerges as important signaling molecules during CO-promoted neuronal differentiation. CO's improvement of neuronal differentiation yield was validated using OHSC as ex vivo model. CORM-A1 treatment of OHSC promoted higher levels of cells expressing the neuronal marker Tuj1. Still, CORM-A1 increased cell proliferation assessed by ki67 expression and also prevented cell death, which was followed by increased Bcl-2 expression, decreased levels of active caspase-3 and PI uptake. Likewise, ROS signaling emerged as key factors in CO's increasing number of differentiated neurons in OHSC. In conclusion, CO's increasing number of differentiated neurons is a novel biological role disclosed herein. CO improves neuronal yield due to its capacity to reduce cell death, promoting an increase in proliferative population. However, one cannot disregard a direct CO's effect on specific cellular processes of neuronal differentiation. Further studies are needed to evaluate how CO can potentially modulate cell mechanisms involved in neuronal differentiation. In summary, CO appears as a promising therapeutic molecule to stimulate endogenous neurogenesis or to improve in vitro neuronal production for cell therapy strategies.

Project description:Carbon monoxide (CO) is an endogenous signaling molecule with demonstrated pharmacological effects. For studying CO biology, there is a need for sensitive and selective fluorescent probes for CO as research tools. In developing such probes, CO gas and/or commercially available metal-carbonyl-based "CO-releasing molecules" (CORMs) have been used as CO sources. However, new findings are steadily emerging that some of these commonly used CORMs do not release CO reliably in buffers commonly used for studying such CO probes and have very pronounced chemical reactivities of their own, which could lead to the erroneous identification of "CO probes" that merely detect the CORM used, not CO. This is especially true when the CO-sensing mechanism relies on chemistry that is not firmly established otherwise. Cu2+ can quench the fluorescence of an imine-based fluorophore, DPHP, presumably through complexation. The Cu2+-quenched fluorescence was restored through the addition of CORM-3, a Ru-based CORM. This approach was reported as a new "strategy for detecting carbon monoxide" with the proposed mechanism being dependent on CO reduction of Cu2+ to Cu1+ under near-physiological conditions ( Anal. Chem. 2022, 94, 11298-11306). The study only used CORM-3 as the source of CO. CORM-3 has been reported to have very pronounced redox reactivity and is known not to release CO in an aqueous solution unless in the presence of a strong nucleophile. To assess whether the fluorescent response of the DPHP-Cu(II) cocktail to CORM-3 was truly through detecting CO, we report experiments using both pure CO and CORM-3. We confirm the reported DPHP-Cu(II) response to CORM-3 but not pure CO gas. Further, we did not observe the stated selectivity of DPHP for CO over sulfide species. Along this line, we also found that a reducing agent such as ascorbate was able to induce the same fluorescent turn-on as CORM-3 did. As such, the DPHP-Cu(II) system is not a CO probe and cannot be used to study CO biology. Corollary to this finding, it is critical that future work in developing CO probes uses more than a chemically reactive "CO donor" as the CO source. Especially important will be to confirm the ability of the "CO probe" to detect CO using pure CO gas or another source of CO.

Dataset Information

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.

Publications

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.

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