The resistance of microorganisms to antibiotics has been developing for more than 2 billion years and is widely distributed among various representatives of the microbiological world. Bacterial enzymes play a key role in the emergence of resistance. Classification of these enzymes is based on their participation in various biochemical mechanisms: modification of the enzymes that act as antibiotic targets, enzymatic modification of intracellular targets, enzymatic transformation of antibiotics, and the implementation of cellular metabolism reactions. The main mechanisms of resistance development are associated with the evolution of superfamilies of bacterial enzymes due to the variability of the genes encoding them. The collection of all antibiotic resistance genes is known as the resistome. Tens of thousands of enzymes and their mutants that implement various mechanisms of resistance form a new community that is called the enzystome. Analysis of the structure and functional characteristics of enzymes, which are the targets for different classes of antibiotics, will allow us to develop new strategies for overcoming the resistance.
More than half of all currently used antibiotics belong to the beta-lactam group, but their clinical effectiveness is severely limited by antibiotic resistance of microorganisms that are the causative agents of infectious diseases. Several mechanisms for the resistance of Enterobacteriaceae have been established, but the main one is the enzymatic hydrolysis of the antibiotic by specific enzymes called beta-lactamases. Beta-lactamases represent a large group of genetically and functionally different enzymes of which extended-spectrum beta-lactamases (ESBLs) pose the greatest threat. Due to the plasmid localization of the encoded genes, the distribution of these enzymes among the pathogens increases every year. Among ESBLs the most widespread and clinically relevant are class A ESBLs of TEM, SHV, and CTX-M types. TEM and SHV type ESBLs are derived from penicillinases TEM-1, TEM-2, and SHV-1 and are characterized by several single amino acid substitutions. The extended spectrum of substrate specificity for CTX-M beta-lactamases is also associated with the emergence of single mutations in the coding genes. The present review describes various molecular-biological methods used to identify determinants of antibiotic resistance. Particular attention is given to the method of hybridization analysis on microarrays, which allows simultaneous multiparametric determination of many genes and point mutations in them. A separate chapter deals with the use of hybridization analysis on microarrays for genotyping of the major clinically significant ESBLs. Specificity of mutation detection by means of hybridization analysis with different detection techniques is compared.
Urinary tract infection (UTI), which is typically caused by Escherichia coli (E. coli), is an insufficiently recognized co-morbidity among patients with chronic obstructive pulmonary disease (COPD). Adequate treatment can be complicated by resistance of the causative pathogen to beta-lactam antibiotics, which often produce beta-lactamase enzymes that destroy the antibiotic. The beta-lactamase family of enzymes is extremely diverse, including different types of enzyme and mutant forms. In this study, we analyzed 580 patients with COPD (236 females and 344 males) and thus found 218 patients with co-morbid UTIs, including 58 patients with UTI caused by E. coli (38 females and 20 males). We also investigated cases of uncomplicated symptomatic and asymptomatic UTI caused by E. coli and the presence of resistance to beta-lactam antibiotics among those patients. The E. coli strains resistant to beta-lactam antibiotics were selected for their ability to grow on selective media, before DNA microarrays were applied for specific identification of three beta-lactamase gene types (i.e., TEM, SHV and CTX-M). Overall, 83% of E. coli strains responsible for UTIs in COPD patients carried extended-spectrum beta-lactamase genes. The most prevalent were those producing CTX-M, with CTX-M-15 being predominant. The rare CTX-M-27 and TEM-15 genes were also detected in two samples. Three samples contained several extended-spectrum beta-lactamase genes simultaneously (CTX-M-15 or CTX-M-14 plus SHV-5 or TEM-15). This high prevalence of resistant E. coli strains necessitates rational antibiotic selection when treating UTI to prevent COPD exacerbations. Additionally, antibiotic therapy should be aligned with and adapted to existing and potential COPD co-morbidities.
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