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bioRxiv · 10.1101/2020.05.15.097816

Differential gene expression and alternation of patterns of DNA methylation in the multidrug resistant strain Escherichia coli ATCC BAA-196 caused by iodine-containing nano-micelle drug FS-1 that induces antibiotic resistance reversion

Korotetskiy, I. S.·Jumagaziyeva, A. B.·Shilov, S. V.·Kuznetsova, T. V.·Suldina, N. A.·Kenesheva, S. T.·Ilin, A. I.·Joubert, M.·Taukobong, S.·Reva, O. N.
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Abstract

BackgroundRecent studies showed promising results on application of iodine-containing nanomicelles, FS-1, against antibiotic resistant pathogens. The effect was studied on Escherichia coli ATCC BAA-196. Materials & methodsRNA sequencing for transcriptomics and the complete genome sequencing by SMRT PacBio RS II technology followed by genome assembly and methylomics study were performed. Results & conclusionsFS-1 treated E. coli showed an increased susceptibility to antibiotics ampicillin and gentamicin. The analysis of differential gene regulation showed that possible targets of iodine-containing particles are cell membrane fatty acids and proteins, particularly cytochromes, that leads to oxidative, osmotic and acidic stresses. Cultivation with FS-1 caused gene expression alterations towards anaerobic respiration, increased anabolism and inhibition of many nutrient uptake systems. Identification of methylated nucleotides showed an altered pattern in the FS-1 treated culture. Possible role of transcriptional and epigenetic modifications in the observed increase in susceptibility to gentamicin and ampicillin were discussed. Lay abstractNew approaches of combatting drug resistance infections are in demand as the development of new antibiotics is in a deep crisis. This study was set out to investigate molecular mechanisms of action of new iodine-containing nano-micelle drug FS-1, which potentially may improve the antibiotic therapy of drug resistant infections. Iodine is one of the oldest antimicrobials and until now there were no reports on development of resistance to iodine. Recent studies showed promising results on application of iodine-containing nano-micelles against antibiotic resistant pathogens as a supplement to antibiotic therapy. The mechanisms of action, however, remain unclear. The collection strain Escherichia coli ATCC BAA-196 showing an extended spectrum of resistance to beta-lactam and aminoglycoside antibiotics was used in this study as a model organism. Antibiotic resistance patterns, whole genomes and total RNA sequences of the FS-1 treated (FS) and negative control (NC) variants of E. coli BAA-196 were obtained and analyzed. FS culture showed an increased susceptibility to antibiotics associated with profound gene expression alterations switching the bacterial metabolism to anaerobic respiration, increased anabolism, osmotic stress response and inhibition of many nutrient uptake systems. Nucleotide methylation pattern were identified in FS and NC cultures. While the numbers of methylated sites in both genomes remained similar, some peculiar alterations were observed in their distribution along chromosomal and plasmid sequences.

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Korotetskiy, I. S., Jumagaziyeva, A. B., Shilov, S. V., Kuznetsova, T. V., Suldina, N. A., Kenesheva, S. T., Ilin, A. I., Joubert, M., Taukobong, S., Reva, O. N.. 2020-05-16. Differential gene expression and alternation of patterns of DNA methylation in the multidrug resistant strain Escherichia coli ATCC BAA-196 caused by iodine-containing nano-micelle drug FS-1 that induces antibiotic resistance reversion. https://doi.org/10.1101/2020.05.15.097816

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