The cell wall is not a target of currently used therapeutics as Mycobacterium are considered naturally resistant to most β-lactam antibiotics. Therefore, combinations of conventional antibiotics with antibiotic activity-enhancing compounds offer a productive treatment strategy and address the widespread emergence of antibiotic-resistant strains. The first area of research was the study of a comparative analysis of disk diffusion testing and the broth dilution method for evaluating the susceptibility of M. smegmatis to antimicrobial agents. A comparative analysis of the susceptibility to antimicrobial agents alone showed that M. smegmatis was the most susceptible to ceftriaxone and kanamycin, and moderately sensitive to vancomycin and prodigiosin. Compared to the susceptibility of the antibacterial combinations, the isolate was not susceptible to antibacterial combinations with prodigiosin in disk diffusion testing. The second area of research was the study of the synergic activity of prodigiosin of S. marcescens and inhibitors of cell wall synthesis manifested by their simultaneous effect on M. smegmatis. The greatest increase in the sensitivity of test-culture of mycobacteria occurred with ampicillin, benzylpenicillin, cephazolin and ceftriaxone in combination with prodigiosin of S. marcescens. The presented combination of antibiotics and prodigiosin reduce the required concentration of the antibiotic and by amplifying the effect of compounds inhibiting cell wall synthesis, thereby giving lower FICI values. These data indicate the possibility of using prodigiosin as a promising candidate for the development of "accompaniment-preparations" for antibiotics for the additional therapy of infectious diseases caused by Mycobacterium spp. and can suspend the likelihood of developing resistance to antibiotics. The cell wall is not a target of currently used therapeutics as Mycobacterium are considered naturally resistant to most β-lactam antibiotics. Therefore, combinations of conventional antibiotics with antibiotic activity-enhancing compounds offer a productive treatment strategy and address the widespread emergence of antibiotic-resistant strains. The first area of research was the study of a comparative analysis of disk diffusion testing and the broth dilution method for evaluating the susceptibility of M. smegmatis to antimicrobial agents. A comparative analysis of the susceptibility to antimicrobial agents alone showed that M. smegmatis was the most susceptible to ceftriaxone and kanamycin, and moderately sensitive to vancomycin and prodigiosin. Compared to the susceptibility of the antibacterial combinations, the isolate was not susceptible to antibacterial combinations with prodigiosin in disk diffusion testing. The second area of research was the study of the synergic activity of prodigiosin of S. marcescens and inhibitors of cell wall synthesis manifested by their simultaneous effect on M. smegmatis. The greatest increase in the sensitivity of test-culture of mycobacteria occurred with ampicillin, benzylpenicillin, cephazolin and ceftriaxone in combination with prodigiosin of S. marcescens. The presented combination of antibiotics and prodigiosin reduce the required concentration of the antibiotic and by amplifying the effect of compounds inhibiting cell wall synthesis, thereby giving lower FICI values. These data indicate the possibility of using prodigiosin as a promising candidate for the development of "accompaniment-preparations" for antibiotics for the additional therapy of infectious diseases caused by Mycobacterium spp. and can suspend the likelihood of developing resistance to antibiotics.
Biopigment are natural compounds (secondary metabolite) produced by many organisms represent one of the important sources of potential lead compounds. Prodigiosin (5[(3-methoxy-5-pyrrol-2-ylidene-pyrrol-2-ylidene) is a red, tripyrrole, water insoluble, bioactive pigment produced by number of different bacteria, actinomycetes and some fungi [1]. Notwithstanding the scarce knowledge of its mechanism of action, prodigiosin appears as a pluripotent molecule, with various health-related properties; the most important being: an anticancer agent [2,3], an immunosuppressant, an antiprotozoal and an antibacterial agent [2,4,5]. Nevertheless, the antimicrobial properties of prodigiosin have often been questioned, particularly because of the high concentrations required for it to be effective, as these exceed the levels causing toxicity in mammalian cells. For this reason, it has been studied in greater depth for its use in anticancer and immunosuppressive therapy, than as an agent to fight infectious agents [2,3,6]. The rate of emergence of fungicide resistance is greater than the pace of fungicide discovery, and the long registration process for new compounds adds further delays. This situation parallels the situation for antibiotics. Increased research activity is thus needed to develop new antifungal drugs [7]. Therefore, combination therapy is a new option for combating such pathogens. Combinations of antibiotics with non-antibiotic activity-enhancing compounds offer a productive strategy to address the widespread emergence of antibiotic-resistant strains [8]. Materials and methods. As a pigment producer, we used the species S. marcescens, namely the pigment-forming strain, which isolated in the laboratories of the Department of Microbiology, virology, and immunology of Bogomolets National Medical University from the bentonite clays of Kurtsivskyi deposit (Crimea, Ukraine). Aspergillus niger ATCC 704 was evaluated against four antifungal agents that included 2 polyene antimycotics: amphotericin B (AMB) and nystatin (NYS), and 2 azole antifungals: intraconazole (INZ) and fluconazole (FNZ) in combination with prodigiosin pigment (PG), using the method of broth microdilution. The MICs of AMB, ITZ, NYS and FNZ (HiMedia Laboratories, Mumbai, India) were determined following the recommendations of the EUCAST protocol for filamentous fungi [9]. All antifungal drugs (except for FNZ, which solubilized in sterile water) were solubilized in dimethyl sulfoxide (DMSO) and the working solutions were prepared in RPMI 1640 medium with 2% glucose, L-glutamine and a pH indicator but
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