Аннотация:In recent years, bacterial resistance has become increasingly important for health care. With a simultaneous decrease in the number of registered antibacterial drugs, resistance to them is growing at an ever-higher rate, which makes the development of new drugs an expensive and ineffective undertaking. Therefore, creation of effective new antibacterial drugs is the most important task of modern Drug Development. Recently, several antibacterial drugs have been discovered; however, there are restrictions on the spectrum of action on bacteria. However, for one of them [1, 2], the spectrum of action opened up as the antibiotic was being studied, from acting only towards gram-positive bacteria [1], to acting on any bacteria, with the exception of those -which had a certain AcrAB-TolC multidrug resistance pump [2, 3]. Mitochondria-targeted antioxidant SkQ1 is a member of a new class of antibiotics that directly affect bacterial bioenergetics. It has been shown to be effective against gram-positive and gram-negative bacteria other than Escherichia coli [2]; resistance of E. coli was determined by the presence of the AcrAB-TolC MDR pump [2, 3]. In our studies, we analyzed all pumps containing TolC in relation to SkQ1 under conditions close to physiological in the cell, and we figured out that (1) SkQ1 is expelled from cells by only one multidrug resistance pump AcrAB-TolC, (2) AcrA protein is necessary for the formation of an active AcrAB-TolC pump, (3) AcrD protein (ortholog of AcrB protein with 66% sequence identity) is unable to pump out SkQ1 from bacterial cells. All Escherichia coli strains demonstrated identical resistance to SkQ1 [3, 4]. We might assume that the presence of the AcrAB-TolC pump means the presence of SkQ1 resistance, but this is not the case. Gram-negative bacteria Rhodobacter sphaeroides and Photobacterium phosphoreum demonstrated sensitivity to SkQ1 also contained an AcrAB-TolC pump. AcrB protein sequences from R. sphaeroides and P. phosphoreum demonstrate only 33% and 65% identity, respectively, to the AcrB protein sequence from E. coli, which is similar to identity between AcrB and AcrD proteins. This allows us to assume that with less than 66% sequence identity of the AcrB protein, resistance to SkQ1 cannot be expected. This is confirmed by the fact that bacteria Klebsiella pneumoniae having an identity of 91.5% also demonstrates resistance comparable to E. coli. Pumps appear to have a set of unique substrates, by which we mean a molecule or a group of molecules with similar structural patterns that are recognized by only one pump in a cell. If a unique pump substrate is available, a functionally identical pump will remove it regardless of its sequence identity. Lack of substrate specificity for unique substrates will indicate that the pump is no longer the same. Thus, proteins AcrB and AcrD from E. coli are genetic and functional paralogs, and proteins AcrB from E. coli and K. pneumoniae are genetic and functional orthologues. In turn, the AcrB proteins from E. coli, R. sphaeroides, and P. phosphoreum may be genetically orthologous, but functionally they are paralogs [5].