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
Recent studies have demonstrated that antibiotic resistance in pathogenic bacteria could be reverted to the drug sensitive phenotype by the treatment with the newly introduced iodine containing nanomolecular complex, FS 1. Antibiotic resistance reversion has been verified as a promising therapeutic approach to combat multidrug resistant infections. The mechanisms of action, however, remain unclear. A 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. The FS 1 treated culture and the negative control variant were sequenced by PacBio RS II System following the SMRTbell 20 kb library preparation protocol. Total RNA samples of these strains were sequenced by Ion Torrent. It was shown that the treatment with FS 1 caused a profound gene expression alternation switching the bacterial metabolism to anaerobic respiration, increased anabolism, oxidative/acidic stress response and an inhibition of many nutrient uptake systems. All this leads to an increase in the susceptibility to antibiotics even when FS 1 is removed from the medium. The later fact implies an involvement of epigenetic mechanisms in gene regulation and antibiotic resistance reversion. This hypothesis was investigated by base call kinetic analysis in PacBio reads and DNA methylation profiling in the sequenced genomes. Several DNA motifs of adenosine and cytosine methylation were identified. While the numbers of methylated sites in chromosomes and plasmids of both genomes, NC and FS, were similar, the distribution of the methylated sites was different. It may explain the observed long lasting effect of the treatment of E. coli with FS 1 on antibiotic susceptibility of this model microorganism.