A novel antivirulent compound fluorothiazinone inhibits Klebsiella pneumoniae biofilm in vitro and suppresses model pneumonia.

The problematic treatment of infections caused by multiple-resistant Klebsiella, especially in ICU, is the leading cause of prolonged hospitalization and high mortality rates. The use of antibiotics for the prevention of infections is considered unreasonable as it may contribute to the selection of resistant bacteria. In this regard, the development of drugs that will be effective in preventing infection during various invasive procedures is extremely necessary. We have shown that the developed innovative antibacterial compound fluorothiazinone (FT) that suppresses the formation of biofilms is effective in the prevention of a model pneumonia caused by a multi-resistant clinical K. pneumoniae isolate. Prophylactic use followed by treatment with FT in mice with acute pneumonia modulates the local innate immune response without suppressing protective properties in the early stages of infection, while contributing to a decrease in the bacterial load in the organs and preventing lethal pathological changes in the lungs at later stages of K. pneumoniae infection. Further development of such antivirulence drugs and their use will reduce morbidity and mortality in nosocomial infections, as well as reduce the number of antibiotics used.

Fluorothiazinon inhibits the virulence factors of uropathogenic Escherichia coli involved in the development of urinary tract infection.

Uropathogenic Escherichia coli (UPEC) is the most common pathogenic bacterium associated with urinary tract infection. Due to the development of antibiotic resistance and MDR, UPEC infection has become a serious problem in the last decade. In order to combat resistance, it is necessary to develop innovative antimicrobial agents that act by different mechanisms than conventional antibiotics. Among the new therapeutic strategies, suppression of pathogen virulence has become a promising alternative, since it fundamentally reduces selective pressure and the development of resistance. In our study, we showed that the compound Fluorothiazinon suppressed UPEC's ability to form biofilms and to move using the flagellum, as well as to penetrate into cells. Prophylactic use with subsequent treatment of FT in rodent models led to an improvement in survival and significantly reduced the bacterial load in the organs of the urinary system, thereby inhibiting the development of ascending infection and preventing the development of pathological changes in prostate tissues. These results suggest that FT affects several UPEC virulence factors at once and if similar results can be found in clinical trials it can potentially be used as a new drug against UPEC.

[Modern aspects of diagnostics of chronic chlamydiosis caused by persisting forms of Chlamydia].

AIM: To study the possible hematogenic route of dissemination of Chlamydia trachomatis and to analyze efficacy of methods of pathogen detection in clinical specimens (sera and scraping material). MATERIALS AND METHODS: Cultural method, electron microscopy, real-time PCR, immunofluorescent assay. RESULTS: C. trachomatis was detected in blood by using 2 tests (culture and PCR) in 95.2% of patients with confirmed Chlamydia infection. Chlamydia isolated from blood had infectious properties that could point to the presence of weakly studied hematogenic route of dissemination of C. trachomatis in host's organism. Study of diagnostic value of pathogen detection in serum showed that in case of chronic diseases of urogenital tract as well as extragenital diseases, rate of C. trachomatis detection in serum was significantly higher (61.1% of cases compared to 16.7% in scraping material). CONCLUSION: It is the first time when data about possible circulation of C. trachomatis in blood of patients was obtained. Detection of C. trachomatis in serum of patients with chronic and complicated forms of chlamydiosis provides essentially new approach for direct identification of the pathogen irrespectively from localization of infection's locus.

Development of Chlamydial Type III Secretion System Inhibitors for Suppression of Acute and Chronic Forms of Chlamydial Infection.

The Type III secretion system (T3SS) is currently considered to be one of the main pathogenicity factors in Gram-negative bacteria, which exhibit different types of parasitizing activity. The presence of this structure is essential for the development of an acute infection; the chronicity of the infection is fundamentally dependent upon its functioning. In this regard, T3TS is one of the most promising targets for the development of broad-spectrum antimicrobial drugs that do not develop resistance and are efficacious for the acute and chronic forms of infection. The mechanism of action in drug development is based on the specific inhibition of T3SS, which should interrupt the infectious process, thereby enabling the immune system to eliminate the pathogen. As a result of pilot screening using specific cellular and bacterial tests, followed by chemical optimization and detailed characterization of the biological activity, a new class of chlamydial T3SS inhibitors was obtained. The selected compounds have obvious advantages over the currently available inhibitors of T3SS pathogens thanks to the high inhibitory activity of these compounds with minimal damaging effects on eukaryotic cells. Preclinical trials of the selected inhibitors are currently under way.