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    Resistance factors of bacterial nosocomial infections causative agents as background for the modern antimicrobials development
    (Igor Sikorsky Kyiv Polytechnic Institute, 2023) Wu Lin; Todosiichuk, Tetіana Serhiyivna
    Wu Lin. Resistance factors of bacterial nosocomial infections causative agents as background for the modern antimicrobials development – qualification scientific work on manuscript rights. Thesis for the degree of Doctor of Philosophy in specialty 091 – Biology. National Technical University of Ukraine "Igor Sikorsky Kyiv Polytechnic Institute", Kyiv, 2023. The relevance of the research. The era of antibiotics, which began with the discovery of penicillin in the ХХ century, may soon end and humanity will face a challenge to overcome which will have to find new solutions. This challenge is now the "era of antibiotic resistance", caused not only by evolutionary mechanisms of protection of pathogens, but also by many factors of human activity. Particular importance are methods of combating infectious agents when they are in treatment centers and a large number of people can both become infected and be a source of their spread. Such infections are nosocomial (hospital-acquired infection) and are defined by World Organization of Health (WHO) as infections that can infect the patient during treatment in hospital or other health care facilities. The sources of infection in hospitals are not only other patients and staff, but also surfaces, instruments, medical manipulations and operations, which is cause to problems in ensuring proper conditions. However, one of the important factors in the treatment of nosocomial infections is their resistance to many antibiotics used in hospitals at the same time, and as a result “superbug” arise, for which there is no effective counteraction. WHO defines a list of such relevant "superbugs", and almost half of them are included in the already established acronym ESCAPE – Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. It was found that the natural and induced variability of microorganisms that cause inflammatory processes can lead to increased resistance to the action of previously effective antiseptics due to the acquisition of resistance. In addition, the selection of resistant forms of microbial pathogens, can cause low efficiency of therapy, severe disease, long-term treatment or, in some cases, the inability to overcome the infection at all. The mentioned and many other sources, citing WHO and the Center for Disease Control (CDC, USA), state that the need to develop effective antimicrobials against these and other nosocomial infections is a "need of the hour". Obviously, the solution of the problem of overcoming nosocomial infections has many dimensions, including organizational, educational, medical and so on. But these long-term strategies do not remove the urgent task of finding effective antimicrobials or new combinations to treat these severe, often combined infections, right today. This work currently involves a large number of scientists and practitioners, with different approaches to the solvation of the problem. One of the most effective method is undoubtedly the identification of the most vulnerable sites of infectious agents and their application as targets for new drugs. Such vulnerable points of microbial pathogens mainly determine their resistance and pathogenicity, and therefore these factors should be considered more closely to find the target. Therefore, the systematization of scientific data and results in this regard, the analysis and evaluation of the main factors of pathogenicity and resistance of nosocomial and other infections are relevant to determine modern approaches to the development of the latest antimicrobial agents. The goal of the work was to justify systemic approaches to the development of modern antimicrobials based on the analysis of resistance factors of bacterial pathogens of nosocomial infections. To achieve the goal, it was necessary to solve the following problems: - on the basis of theoretical analysis and research, determine the factors and mechanisms of resistance of microbial pathogens, which can be chosen as targets for the action of antiseptics; - to establish the molecular-genetic characteristics of individual representatives of bacterial pathogens that can be used to counter their distribution and to select strategies for antimicrobial therapy; - to propose a method of screening antimicrobial substances for selected pathogenesis targets of pathogenic bacteria, which can be applied in research practice; - to show the prospects of creating effective antiseptics based on microbial products - antibiotics and enzymes of the streptomycete Streptomyces albus; - to develop recommendations for the implementation of methods of monitoring the resistance of nosocomial infections and the principles of modern antimicrobials development. Scientific novelty of the obtained results. The following scientific results were obtained for the first time in the dissertation: - on the basis of genome sequencing and gene annotation of the strain Bacteroides thetaiotaomicron DSMZ 2079 isolated from the patient's blood, the presence of a one- and two-component system for recognizing environmental signals and responding to them was shown, the presence of four homologs of the selftransmitted conjugative transposon CTnDOT, which provides the extension of resistance to tetracycline and erythromycin. The rpoB and tuf genes (in the JHR92_RS03155 and JHR92_RS03195 loci, respectively), which determine the strain's resistance to antibiotics, were identified; - based on the results of the analysis of the 16S rRNA sequences of the isolated clinical strain Pseudomonas oryzihabitans JN 873340 and its comparison with 29 other strains of the species from GenBank, a phylogenetic tree was built and the possibility of identifying their geographical origin by two hypervariable regions V4 and V5 was shown; - the minimum inhibitory concentrations of the new streptofungin antibiotic against C. albicans ATCC 10231 (10 μg/ml), B. subtilis ATCC 6633 (200 μg/ml) and P. aeruginosa ATCC 9027 (500 μg/ml) were established, as well as the absence of toxicity in a wide range of concentrations (from 2.5 to 500 μg/ml), which determines its potential as an active pharmaceutical ingredient; Practical significance of the obtained results. The practical significance of the dissertation consists in solving the scientific and practical problem of developing antimicrobial agents that do not cause the resistance development of microbial pathogens. The developed method for screening inhibitors of sortase A, which is distinguished by the use of cheaper substrates and, accordingly, the possibility of wide application, has been implemented in the practice of the Environmental Comprehensive laboratory of the School of Tropical Medicine of Hainan Medical University, China. (Act of implementation dated September 4, 2023). Developed "Recommendations for the implementation of methods of resistance control of nosocomial infections and principles of development of modern antimicrobial drugs", approved (08.25.23) at the Shupyk National Healthcare University of Ukraine, for use in practice. Proposed as a result of the dissertation research the principles and approaches for the creation of preparations based on biologically active substances with different mechanisms of action were used in the production program of LLC "PHARMA INTERNATIONAL GROUP 2" (Kyiv) in the development of functional cosmetics (Instructions for use dated 20.07.2023 r.). The results of the work were implemented in the teaching of the courses "General microbiology and virology" and "Fundamentals of pharmaceutical production" for students of the specialty 162 "Biotechnology and bioengineering" at the department of industrial biotechnology and biopharmacy of KPI named after Igor Sikorskyi (Act of implementation dated 20.09.2023), as well as for students of the specialty "Tropical medicine" within the framework of lectures and laboratory (practical) classes in the disciplines "Medical immunology", "Pathobiology", "Medical microbiology", "Environmental microbiology ", "Hygienic microbiology", "Environment and health" at Hainan Medical University (China) (Act of implementation dated 01.09.2023). The main provisions of the work are presented in 10 scientific papers: 4 scientific articles included in the Scopus scientometric database, including 2 of them in publications assigned to the 2nd quartile (Q2) in accordance with the SCImago Journal and Country Rank classification (equal to two publications that are counted in accordance with the first paragraph of paragraph 11 of the Resolution of the Cabinet of Ministers of Ukraine dated March 6, 2019 No. 167); 4 articles in specialized foreign periodicals; 2 abstracts at all-Ukrainian and international conferences.