Current Topics on Multiple Drug Resistance from Microbes to Humans

Dear Colleagues,

In the course of evolution, living organisms have developed multiple mechanisms of response to harmful chemicals present in the environment. These substances may attack genes (via modification and degradation of DNA), proteins, phospholipids, sugars and other intracellular components (via sets of modification reactions including radical oxidation). Toxic attack of these substances leads to cell death in the case of lethal concentration. Sub-lethal concentrations of such substances may induce cell adaptation to toxic stress, which will lead to decreased cellular sensitivity. Under permanent sublethal toxic pressure cells are able to respond via activation of diverse well-defined cell defensive pathways. Activation of cell defense pathways subsequently leads to increase of cells' resistance to different chemicals often with principally diverse structures and mechanisms of action. Almost all cell types could respond by this way. Development of drug resistance represents a real obstacle in antimicrobial and anticancer treatment. The above described decrease of cells' sensitivity to various unrelated drugs is known as multidrug resistance (MDR). Xenobiotic detoxification involves step-by-step mechanism (detoxification phase I-III). The first step is conversion of the hydrophobic nature of molecules (which allows the molecule to be easily transported through the cell membrane) to metabolic intermediates that are more water – soluble. The transforming enzymes alter compounds by oxidation, reduction or hydrolysis, to make them either more readily excretable or less pharmacologically active. These reactions are mediated by the versatile cytochrome P450 (CYP) enzymes and the more selective flavin-containing monooxygenases, monoamine oxidases. Altered compounds are subject of conjugation enzymes in the process of glucuronidation, acetylation, sulfation, glutathione conjugation, acetylation, aminoacyl conjugation or methylation by conjugating enzymes of II detoxification phase. These processes are adjusting the toxic compounds as substrates for the membrane transporters (predominantly from ABC and MFS family) that ensure their transport out of the cell. These membrane transporters are known as systems of III phase of detoxification.

In addition to drug modification/elimination under phase I-III of cell detoxification, tolerance/resistance of cells against toxic compound could be influenced by alteration in ER stress development, cell death progression, DNA repair, epigenetics regulation and others. Parallel to these mechanisms the balance in prooxidation/antioxidation status of cells represent another important feature responsible for capability of cells to enter the process of death.

We are looking forward to your contributions to this Special Issue.

Prof. Dr. Albert Breier
Assoc. Prof. Dr. Petra Olejníková
Dr. Zdena Sulová
Guest Editors

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• MDR
• MDR in leukemia ABC transporters ER stress and MDR Altered protein glycosylation in MDR leukemia