Synthesis of novel isothiazolopyridines and their in vitro evaluation against Mycobacterium and Propionibacterium acnes

AbstractIn this paper we describe synthesis, structures and some physicochemical properties of 20 isothiazolopyridines 8–13 substituted differently into an isothiazole ring as well as their in vitro antibacterial assays against Mycobacterium tuberculosis H37Rv, Mycobacterium fortuitum PCM 672 and Propionibacterium acnes PCM 2400. Compound 13a was found to be the most active derivative against M. tuberculosis H37Rv, demonstrating 100% growth inhibition of microorganisms in the primary screen (minimum inhibitory concentration [MIC] 6.25μg/mL). Nineteen of the prepared compounds were evaluated against M. fortuitum PCM 672 and P. acnes PCM 2400 and only compounds 9 and 12d exhibited excellent activity against individual strains of microorganisms with MIC90 <1μg/mL. The inhibitory action of the remaining isothiazolopyridines towards the tested strains of the microorganism was low, absent, or a non-linear correlation prohibited accurate determination of MIC values. Unexpectedly, seven of the remaining isothiazolopyridines tested against M. fortuitum and P. acnes stimulated growth of the microorganisms in the range 10–50% or even more (10b) under experimental conditions

INSIGHTS INTO MYCOBACTERIAL ACTIVITY AND CYTOTOXICITY OF SUBSTITUED ISOXAZOLE-4-CARBOHYDRAZIDE DERIVATIVES.

The purpose of this study was to evaluate the antimycobacterial activity of novel derivatives of 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide 1, isoniazid (INH) structural analogue. A set of 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide 1 derivatives 2a-j have been obtained by condensation reactions with aldehydes and further transformed by cyclization with corresponding orthoesters to 5-amino-3-methylisoxazole[5,4-d]pyrimidin-4-one derivatives 3a-j and 4a-j. From the structural and functional point of view, all these products proved to be biologically important and could be used as substrates for further synthesis. 21 out of 31 structures were newly developed. Described compounds were screened against Mycobacterium fortuitum in MABA test. The most active compound 2e, 2g revealed minimum inhibitory concentration at 16 μg/ml. In addition, these compounds revealed low cytotoxicity against lung (A549) and fibroblasts (L929) cell lines. The results demonstrated the potential and importance of further development of 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide derivatives as a new class of antimycobacterial compounds

Faecal microbiota and fatty acids in feline chronic enteropathy

Abstract Background Feline chronic enteropathy is a set of disorders defined as the presence of clinical signs of gastrointestinal disease for at least three weeks. The most common final diagnoses are inflammatory bowel disease and alimentary small cell lymphoma. The etiopathogenesis of these diseases is incompletely understood; however, it is hypothesised that they involve a combination of factors, including altered composition and/or functionality of the intestinal microbiome. An important factor in the interplay of the microbiome and host is the production of short- and branched-chain fatty acids.  The aim of this study was to evaluate the possible differences in faecal microbiota diversity, composition and fatty acid production between cats suffering from chronic enteropathy and healthy cats. Sixteen cats suffering from chronic enteropathy and fourteen healthy control cats were enrolled in the study. The microbiota compositions of faecal samples were analysed by using next-generation amplicon sequencing of the V3V4 fragment of the 16S rRNA gene. Fatty acids were evaluated by high-performance liquid chromatography. Results Both the alpha and beta diversities were significantly lower in samples obtained from cats with chronic enteropathy. The relative abundance of the phylum Proteobacteria, orders Lactobacillales and Enterobacterales, family Enteriobacteriaceae and genus Escherichia Shigella were higher in diseased cats, whereas the abundance of the phylum Bacteroidota and order Peptococcales were higher in control cats. The faecal concentrations of short-chain fatty acids were higher in cats with chronic enteropathy, with lower propionate proportions and higher butyrate proportions. Conclusion The study revealed alterations in microbiota compositions and short-chain fatty acid concentration in cats suffering from chronic enteropathy, which is an important finding both for research on the pathogenesis of the disease and for potential therapeutic interventions in the form of faecal microbiota transplantation and/or probiotic supplementation

Homeostasis of the Intestinal Mucosa in Healthy Horses&mdash;Correlation between the Fecal Microbiome, Secretory Immunoglobulin A and Fecal Egg Count

The defensive function of the intestinal mucosa depends both on the ability to secrete immunoglobulin A and communication with the mucus microbiome. In horses, the functioning of this system is also influenced by the presence of nematode eggs. Feces collected from healthy horses were examined to determine the fecal egg count, immunoglobulin A level (ELISA), microbiome composition (Next-Generation Sequencing, NGS, V3&ndash;V4 and V7&ndash;V9 hypervariable regions of the 16S rRNA gene analysis and short-chain fatty acid (SCFA) production ((high-performance liquid chromatography, HPLC). In the taxonomic analysis within the phylum, the following order of dominance was found: Firmicutes, Bacteroidota, Verrucomicrobiota and Fibrobacterota. The coefficient of phylogenetic diversity of the microbiome positively correlated with both secretory immunoglobulin A (SIgA) [&mu;g/g of feces] (p = 0.0354, r = 0.61) and SIgA [&mu;g/mg of fecal protein] (p = 0.0382, r = 0.6) and with the number of Cyathostomum eggs (p = 0.0023, r = 0.79). Important components of the key microbiome in horses, such as phylum Proteobacteria and species Ruminococcus flavefaciens, were positively correlated with the fecal SIgA (p &lt; 0.05). All the obtained results indicate the existence of significant relationships between the host response (SIgA production) and composition and SCFA production in the microbiome as well as the presence of small strongyles in the digestive tract of horses