Comparison of transcriptional responses and metabolic alterations in three multidrug resistant model microorganisms,Staphylococcus aureusATCC BAA-39,Escherichia coliATCC BAA-196 andAcinetobacter baumanniiATCC BAA-1790, on exposure to iodine-containing nano-micelle drug FS-1

Abstract

Iodine is one of the oldest antimicrobial agents. Till now there have been no reports on development of resistance to iodine. Recent studies showed promising results on the application of iodine-containing nano-micelles, FS-1, against antibiotic resistant pathogens as a supplement to antibiotic therapy. The mechanisms of action, however, remain unclear. The aim of this study was to perform a systemic analysis of gene regulation and metabolic alterations in three phylogenetically distant reference strains from ATCC culture collection representing multidrug resistant pathogens associated with nosocomial infections: Escherichia coli BAA-196, Staphylococcus aureus BAA-39 and Acinetobacter baumannii BAA-1790. These cultures were treated in 5 min exposure to sublethal doses of the iodine-containing drug FS-1 applied in the late lagging and the mid of the logarithmic growth phases. Complete genome sequences of these strains were obtained in previous studies. Gene regulation was studied by total RNA extraction and Ion Torrent sequencing followed by mapping the RNA reads against the reference genome sequences and statistical processing of read counts using the DESeq2 algorithm. It was found that the treatment of bacteria with FS-1 profoundly affected the expression of many genes involved in central metabolic pathways; however, alterations of gene expression profiles were species-specific and depended on the growth phase when the drug was applied. Disruption of respiratory electron-transfer membrane complexes, increased penetrability of bacterial cell wall, osmotic and oxidative stresses leading to DNA damage were the major factors influencing the treated bacteria.IMPORTANCEInfections caused by antibiotic resistant bacteria threaten public health worldwide. Combinatorial therapy when antibiotics are administrated together with supplementary drugs improving susceptibility of pathogens to regular antibiotics is considered as a promising way to overcome this problem. An induction of antibiotic resistance reversion by the iodine-containing nano-micelle drug FS-1 was reported recently. This drug is currently under clinical trials in Kazakhstan against multidrug resistant tuberculosis. The effect of iodine solutes on metabolic and regulatory processes in bacterial cells remain unexplored that precludes the effective application of iodine-containing antimicrobials in medicine. The current work provides an insight into gene regulation in antibiotic resistant bacteria treated with iodine-containing nanoparticles. Our expectation is that this study will shed light on unexplored bioactivities of iodine and the mechanisms of its antibacterial effect when applied in low concentrations. This knowledge will aid in future design of new drugs against antibiotic resistant infections.