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.

Metal-based carbon monoxide releasing molecules with promising cytotoxic properties

“…79 CORM-2 can regulate a variety of genes with roles in intestinal inflammation and tumour development. 80 CORM-2 has also other potential medicinal applications, including cardioprotective, 81 antimicrobial, [82][83][84][85][86] analgesic, and anti-nociceptive actions, 87 anti-apoptotic, 88 and angiogenic capabilities. 89 Also, it possesses CO-mediated protective effect to the kidney against ischemic injury.…”

Hydrogen Sulfide and Carbon Monoxide Tolerance in Bacteria

“…In general, the transcriptome alteration shared similarities with those observed for E. coli under oxidative stress (e.g., induction of members of the SoxRS regulon). Interestingly, in uropathogenic E. coli isolates, CORM-2 induced up-regulation of some virulence genes [ 81 , 82 ].…”