Drug induced reversion of antibiotic resistance is a promising way to combat multidrug resistant infections. However, lacking knowledge of mechanisms of drug resistance reversion impedes employing this approach in medicinal therapies. Induction of antibiotic resistance reversion by a new anti-tuberculosis drug FS-1 has been reported. FS-1 was used in this work in combination with standard anti-tuberculosis antibiotics in an experiment on laboratory guinea pigs infected with an extensively drug resistant (XDR) strain M. tuberculosis SCAID 187.0. During the experimental trial, genetic changes in the population were analyzed by sequencing of M. tuberculosis isolates followed by variant calling. In total 11 isolates obtained from different groups of infected animals at different stages of disease development and treatment were sequenced. It was found that despite the selective pressure of antibiotics, FS-1 caused a counter-selection of drug resistant variants that speeded up the recovery of the infected animals from XDR tuberculosis. Drug resistance mutations reported in the genome of the initial strain remained intact in more sensitive isolates obtained in this experiment. Variant calling in the sequenced genomes revealed that the drug resistance reversion could be associated with a general increase in genetic heterogeneity of the population of M. tuberculosis. Accumulation of mutations in PpsA and PpsE subunits of phenolpthiocerol polyketide synthase was observed in the isolates treated with FS-1 that may indicate an increase of persisting variants in the population. It was hypothesized that FS-1 caused an active counter-selection of drug resistant variants from the population by aggravating the cumulated fitness cost of the drug resistance mutations. Action of FS-1 on drug resistant bacteria exemplified the theoretically predicted induced synergy mechanism of drug resistance reversion. An experimental model to study the drug resistance reversion phenomenon is hereby introduced.

The nature and physicochemical characteristics of nanomaterials affect their biological activity. Sulfur microparticles and sulphur nanoparticles have different levels of activity against bacterial,...

Background: Complexes of iodine (povidone-iodine and cadexomers) are among the most important antiseptics used in clinical and veterinary medicines. However, high local irritation activity and systemic toxicity limits their oral administration. The purpose of the study was to compare the effect of a new complex of iodine (PA, potentiator of anticancer antibiotics), in which iodine is coordinated by carbohydrates and polypeptides) on the organisms of rats and dogs treated orally with the drug for 30 days. Methods: Wistar rats and Beagle dogs served as experimental animal models. Effect of PA on the animal organism was examined through the measurements of hormones level changes, hematological and clinical chemistry parameters alterations, necropsy and histological examination. Results: The established maximum tolerated dose (MTD) of 2,000 mg/kg PA led to a decrease in the rate of body weight gain in male and female rats. Changes in hematological and certain biochemical parameters in rats at doses of 1,000 and 2,000 mg/kg were observed. Histological study of the thyroid gland revealed changes in the shape and size of the follicles along with colloid resorption. Administration of a half of MTD (180 mg/kg) and lower doses did not result in any change in dogs (thyroid-stimulating hormone, triiodothyronine, and thyroxine). Conclusions: The results of our study show that the pathogenetic action of PA takes place along the path of induction of an inflammatory response with the development of thyrotoxicosis, rather than hypothyroidism. The mechanism of induction of an inflammatory response is also confirmed by histological studies of lesions of the thyroid gland and testes in rats (Figure S1). The no-observed-adverse-effect level (NOAEL) of PA is estimated to be 180 mg/kg (or iodine 22.8 mg/kg) in dogs, which is equivalent to 100 mg/kg (or iodine 12.3 mg/kg) in humans.

The new iodine complex (FS-1), including molecular iodine, which is coordinated by lithium, magnesium halides, and bioorganic ligands, possesses high bactericidal activity against various microorganisms, including Mycobacterium sp., Staphylococcus aureus MRSA and MSSA, Escherichia coli, Pseudomonas aeruginosa, etc. FS-1 has synergistic properties with a broad class of antibiotics. The experimental model of tuberculosis in guinea pigs caused by clinical multidrug-resistant strains of Mycobacterium tuberculosis shows antituberculosis, immunomodulatory, and anti-inflammatory activity. FS-1 is characterized by low acute toxicity and lack of genotoxicity and mutagenicity. FS-1 is well distributed to organs and tissues; its pharmacokinetics is linear. The maximum nontoxic dose is 100 mg/kg for rats after 28-day oral administration and 30 mg/kg for rabbits after 180-day oral administration.

SARS-CoV-2 researchers faced the problem of specificity for ACE-2 receptors. In mice and rats, ACE-2 has a low affinity for this virus. In contrast, the Syrian hamster (Mesocricetus auratus) when infected with SARS-CoV-2 show clinical signs of infection with this virus. Therefore, it is necessary to assess the severity of pathological lesions and immune response for relevance to preclinical new drugs against SARS-CoV-2. In this study, we studied blood counts, serum levels of Il-6, TNF-?, IFN-? and IFN-? and the histological state of the lungs of Syrian hamsters. In our study Syrian hamsters showed clinical signs of COVID-19. In infected animals, a decrease in the level of leukocytes and granulocytes was noted. There was some suppression of the immune response, without an increase in the main biomarkers of ARDS. The exception was high levels of TNF-?. Histological examination showed an early exudative phase of moderate ARDS. There were no significant gender differences in the production of pro-inflammatory cytokines. In this study, it was shown that infection with COVID-19 in young Syrian hamsters is modeled with moderate severity, and can be applied in preclinical studies.

This work is devoted to the identification of a mathematical model of bacteria population under the antibiotic influence, based on the solution of the corresponding inverse problems. These problems are solved by the gradient method, genetic algorithm and Nelder–Mead method. Calculations are made using model and real data.