Abstract
Application of supplementary drugs which increase susceptibility of pathogenic bacteria to antibiotics is a promising yet unexplored approach to overcome the global problem of multidrug-resistant infections. The discovery of a new drug, an iodine-containing nano-molecular complex FS-1, which has proven to improve susceptibility to antibiotics in various pathogens, including MRSA strain Staphylococcus aureus ATCC BAA-39TM, allowed studying this phenomenon. Chromosomal DNA and total RNA samples extracted from the FS-1 treated strain (FS) and from the negative control (NC) cultures were sequenced by PacBio SMRT and Ion Torrent technologies, respectively. PacBio DNA reads were used to assemble chromosomal DNA of the NC and FS variants of S. aureus BAA-39 and to perform profiling of epigenetically modified nucleotides. Results of transcriptional profiling, variant calling and detection of epigenetic modifications in the FS variant were compared to the NC variant. Additionally, the genetic alterations caused by the treatment of S. aureus BAA-39 with FS-1 were compared to the results of a similar experiment conducted with another model organism, E. coli ATCC BAA-196. Several commonalities in responses of these phylogenetically distant microorganisms to the treatment with FS-1 were discovered, which included metabolic transition toward anaerobiosis and oxidative/osmotic stress response. S. aureus culture appeared to be more sensitive to FS-1 due to a higher penetrability of cells by iodine bound compounds, which caused carbonyl stress associated with nucleotide damaging by FS-1, abnormal epigenetic modifications and an increased rate of mutations. It was hypothesized that the disrupted pattern of adenine methylated loci within methicillin-resistance chromosome cassettes (SCCmec) may promote excision of this antibiotic resistance determinant from chromosomes while the altered pattern of cytosine methylation was behind the adaptive gene regulation in the culture FS. The selection against the antibiotic resistance in bacterial populations caused by abnormal epigenetic modifications exemplifies possible mechanisms of antibiotic resistance reversion induced by iodine-containing compounds. These finding will facilitate development of therapeutic agents against multidrug-resistant infections.
Highlights
The misuse of antibiotics, as well as inappropriate prescription and overuse, has led to strong selective pressure, resulting in the survival and wide distribution of drug-resistant pathogens that threaten the public health system globally (Barbosa and Levy, 2000; Ventola, 2015)
Bacteria were inoculated into test-tubes with 10 ml of liquid MH medium supplemented with FS-1 (450 μg/ml) that corresponds to 1/2 minimal bactericidal concentration (MBC) of the drug estimated for the strain S. aureus BAA-39
Antibiotic resistance reversion induced by FS-1 was evaluated after cultivation of the multidrug-resistant bacterium for 10 days on the medium containing a sub-lethal 1/2 MBC of FS-1 with daily re-inoculation into fresh medium
Summary
The misuse of antibiotics, as well as inappropriate prescription and overuse, has led to strong selective pressure, resulting in the survival and wide distribution of drug-resistant pathogens that threaten the public health system globally (Barbosa and Levy, 2000; Ventola, 2015). Various factors are involved in the emergence and spread of drug resistant bacteria These factors include mutations, which can modify target proteins; the transfer of genetic material, known as horizontal gene transfer; selective pressure in healthcare and community settings, which facilitates the development and distribution of multiple resistant bacteria; and in some cases, inability to detect emerging resistance phenotypes (Wang et al, 2017; Kumar et al, 2019). It was expected that the physiological cost for bacteria to maintain resistance genes in the absence of antibiotics would be large enough to select substantially against the drug resistance. This has not been generally observed for various reasons. Resistance mutations may provide the resistant strains with a fitness advantage by conferring increased virulence (Roux et al, 2015)
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