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The increasing antibiotic resistance is a severe concern for humanity. Co-cultivation of microorganisms is a promising method for obtaining new secondary antimicrobial metabolites. An effective strategy for co-cultivation of microorganisms involves the usage of certain biological inductors. The aim of this review is to summarize existing scientific research in the literature related to the influence of physiologically different types of biological inductors on the synthesis and biological activity of microbial secondary metabolites. An analysis of the literature has shown that in such studies, either live or inactivated cells of the inductor are added to the culture medium at significantly lower concentrations compared to the producer cells of the final metabolites, or the supernatant (filtrate) after cultivation of a competitive microorganism is used as an inductor. According to the literature and our own experimental studies, the using inductors is an effective approach not only for intensifying the synthesis of bacteriocins, surfactants, and antibiotics, but also for increasing their biological activity. Additionally, it often leads to the production of novel antimicrobial compounds that are not typical for the producer. However, the mechanisms of effect of inductors on the synthesis of biologically active secondary metabolites require further research, as the literature suggests that their introduction into the cultivation medium of producer does not always lead to an intensification of the synthesis of the final product. Moreover, the biological activity of secondary metabolites depends on the cultivation conditions of the producer, including the presence of biological inductors in the culture medium. Therefore, it is essential to conduct further research on the interaction between producers and competitive microorganisms to regulate the biological activity of the synthesised metabolites. In addition, there is a necessity to search for more cost-effective substrates for the biosynthesis of secondary metabolites, optimize the composition of the culture medium and expand the range of both pro- and eukaryotic inductors. [ABSTRACT FROM AUTHOR]

Currently, the effectiveness of technologies for microbial surfactants, which are characterized by a complex of practically valuable physicochemical and biological properties is lower than that of synthetic analogues. To reduce the cost of these products of microbial synthesis, industrial waste is used as substrates for their biosynthesis. In previous studies, it has been established that surfactants synthesized by Acinetobacter calcoaceticus IMV B-7241 on crude glycerol have lower antimicrobial activity compared to that obtained on purified glycerol. The main approaches to the regulation of the biological activity of microbial surfactants are their post-fermentation chemical modification, as well as the improvement of producer strains by methods of metabolic and genetic engineering. In recent years, numerous studies have appeared on the co-cultivation of producers of antimicrobial compounds with competitive microorganisms (biological inductors), in response to the presence of which the antimicrobial activity of the final product increases. Aim. To study the effect of live and inactivated cells of Bacillus subtilis BT-2, as well as the corresponding supernatant, on the antimicrobial and anti-adhesive activity and the ability to destroy biofilms of A. calcoaceticus IMV B-7241 surfactants synthesized in a medium with glycerol of different degrees of purification. Methods. The A. calcoaceticus IMV B-7241 strain was grown in a liquid mineral medium with purified and crude glycerol, into which live and inactivated B. subtilis BT-2 cells as well as the supernatant after growing the B. subtilis BT-2 strain (2.5-10%, v/v) were added. Surfactants were extracted from the supernatant of the culture liquid with Folch's mixture. Anti-adhesive activity and the degree of destruction of biofilms were determined by the spectrophotometric method, and antimicrobial activity -- by the indicator of the minimum inhibitory concentration. The activity of enzymes of surface-active aminolipids biosynthesis (NADP+-dependent glutamate dehydrogenase) and glycolipids (phosphoenolpyruvate (PEP)-carboxylase, PEP-synthetase, PEP-carboxykinase, trehalose-phosphate synthase) was analyzed in cell-free extracts obtained after cells sonication. Results. It was established that the introduction of inactivated B. subtilis BT-2 cells and supernatant into the medium with both substrates did not affect the indicators of the surfactant synthesis, while in the presence of live cells of the B. subtilis BT-2 strain in the medium with purified glycerol, a decrease in the concentration of the final product by 1.5 times, and in the culture medium with crude glycerol -- an increase by 1.4 times were observed compared to the indicators with no inductor. The study of the antimicrobial activity of surfactants showed that the most effective of the used inductors (live, inactivated cells, supernatant) were live cells of B. subtilis BT-2. The introduction of B. subtilis BT-2 strain live cells into the culture medium with both substrates was accompanied by the formation of surfactants, the minimum inhibitory concentrations of which in relation to bacterial (Bacillus subtilis BT-2, Staphylococcus aureus BMS-1, Proteus vulgaris PA-12, Enterobacter cloacae C-8) and yeast (Candida albicans D-6, Candida tropicalis PE-2) test-cultures were 3-23 times lower than established for those synthesized on the medium with no inductor. Anti-adhesive activity of surfactants obtained on purified and crude glycerol in the presence of all types of inductors was higher compared to those synthesized in the culture medium without inductors (cells adhesion of bacterial and yeast test-cultures on polyvinyl chloride was 13-70 and 33-96%, respectively). Introduction of live and inactivated B. subtilis BT-2 cells or the supernatant into A. calcoaceticus IMV B-7241 cultivation medium was accompanied by the synthesis of surfactants, in the presence of which the disruption of bacterial biofilms was on average 10-20% higher compared to using surfactants synthesized without an inductor. In the presence of B. subtilis BT-2 in the medium, in the cells of the A. calcoaceticus IMV B-7241 strain, the activity of NADP+-dependent glutamate dehydrogenase (a key enzyme of aminolipids biosynthesis) increased by 1.5-2 times, while the activity of biosynthesis of glycolipids enzymes remained practically at the same level as without an inductor. Such data indicate that the higher biological activity of surfactants obtained by A. calcoaceticus IMV B-7241 in the presence of biological inductors might be due to an increase in the content of aminolipids in their composition. Conclusions. Th is research has established the possibility of regulating the antimicrobial and anti-adhesive activity as well as the ability to disrupt biofilms of A. calcoaceticus IMV B-7241 surfactants by introducing competitive bacteria B. subtilis BT-2 into the culture medium. It is important that under such cultivation conditions, the antimicrobial activity of surfactants synthesized on toxic crude glycerol significantly increases. [ABSTRACT FROM AUTHOR]

In recent decades overuse and misuse of antibiotics as well as social and economic factors have accelerated the spread of antibiotic-resistant bacteria, making them a major problem for humanity. One of the most effective approaches to the discovery of new secondary antimicrobial metabolites is co-cultivation of microorganisms, in which the producer of the target products is grown together with competitive microorganisms (inductors), in response to the presence of which silent biosynthetic genes of the producer strain are activated and an increase in the biological activity of the synthesized secondary metabolites and/or even the synthesis of new metabolites is observed. The review summarizes the current literature data on the co-cultivation of antimicrobial substances producers with competitive microorganisms, which results in the synthesis of new metabolites with antimicrobial and cytotoxic activity, not typical for monocultures. During the co-cultivation of fungi, bacteria, and fungi with bacteria, the synthesis of new antimicrobial and anticancer metabolites, which are classified as alkaloids, phenylpropanoids, macrolides, polyketides, cyclopeptides, terpenoids, anthraquinones, and steroids, is observed. These data indicate that the mixed fermentation of microorganisms is a simple, cheap, and quite effective way to obtain new metabolites that are promising for use in medicine. [ABSTRACT FROM AUTHOR]