The growing resistance of microorganisms towards antibiotics has become a serious global problem. Therapeutics with novel chemical scaffolds and/or mechanisms of action are urgently needed to combat infections caused by multidrug resistant pathogens, including bacteria, fungi and viruses. Development of novel antimicrobial agents is still highly dependent on the discovery of new natural products. At present, most antimicrobial drugs used in medicine are of natural origin. Among the natural producers of bioactive substances, Actinobacteria continue to be an important source of novel secondary metabolites for drug application. In this review, the authors report on the bioactive antimicrobial secondary metabolites of Actinobacteria that were described between 2011 and April 2018. Special attention is paid to the chemical scaffolds, biological activities and origin of these novel antibacterial, antifungal and antiviral compounds. Arenimycin C, chromopeptide lactone RSP 01, kocurin, macrolactins A1 and B1, chaxamycin D as well as anthracimycin are regarded as the most effective compounds with antibacterial activity. In turn, the highest potency among selected antifungal compounds is exhibited by enduspeptide B, neomaclafungins A-I and kribelloside D, while ahmpatinin i Bu, antimycin A1a, and pentapeptide 4862F are recognized as the strongest antiviral agents.

Bacterial resistance to commonly used antibiotics is constantly increasing. Bacteria particularly dangerous for human life are methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium and fluoroquinolone-resistant Pseudomonas aeruginosa. Hence, there is an incessant need for developing compounds with new modes of action and seeking alternate drug targets. In this review, the authors discuss the current situation of antibacterial medicines and present data on new antibiotic targets. Moreover, alternatives to antibiotics, such as bacteriophages, antimicrobial peptides and monoclonal antibodies, are presented. The authors also draw attention to the valuable features of natural sources in developing antibacterial compounds. The need to prevent and control infections as well as the reasonable use of currently available antibiotics is also emphasized.

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A new metabolite, cyclic dipeptide, cis-(3S,8aS)-3-(3,4-dihydroxybenzyl)hexahydropyrrolo[1,2-a]pyrazine-1,4-dione, named JS-3 was isolated from Streptomyces sp. 8812 fermentation broth. Its chemical structure was established by means of spectroscopic analysis. A wide-range-screening study, which included inhibition assay of DD-carboxypeptidase/transpeptidase activity, determination of antibacterial, antifungal, and antiproliferative activities as well as free-radical scavenging was performed. To authors knowledge, this is the first isolation of such compound from natural sources and the first one from bacteria, Streptomyces.

Cancers are the leading cause of deaths worldwide. In 2018, an estimated 18.1 million new cancer cases and 9.6 million cancer-related deaths occurred globally. Several previous studies have shown that the enzyme, leucine aminopeptidase is involved in pathological conditions such as cancer. On the basis of the knowledge that isoquinoline alkaloids have antiproliferative activity and inhibitory activity towards leucine aminopeptidase, the present study was conducted a study which involved database search, virtual screening, and design of new potential leucine aminopeptidase inhibitors with a scaffold based on 3,4-dihydroisoquinoline. These compounds were then filtered through Lipinski’s “rule of five,” and 25 081 of them were then subjected to molecular docking. Next, three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed for the selected group of compounds with the best binding score results. The developed model, calculated by leave-one-out method, showed acceptable predictive and descriptive capability as represented by standard statistical parameters r2 (0.997) and q2 (0.717). Further, 35 compounds were identified to have an excellent predictive reliability. Finally, nine selected compounds were evaluated for drug-likeness and different pharmacokinetics parameters such as absorption, distribution, metabolism, excretion, and toxicity. Our methodology suggested that compounds with 3,4-dihydroisoquinoline moiety were potentially active in inhibiting leucine aminopeptidase and could be used for further in-depth in vitro and in vivo studies.

A b s t r a c tThe nutritional requirements and environmental conditions for a submerged culture of Streptomyces sp. 8812 were determined. Batch and fed-batch Streptomyces sp. 8812 fermentations were conducted to obtain high activity of secondary metabolites. In the study several factors were examined for their influence on the biosynthesis of the active metabolites-7-hydroxy-6-oxo-2,3,4,6-tetrahydroisoquinoline-3-carboxyl acid (C 10 H 9 NO 4 ) and N-acetyl-3,4-dihydroxy-l-phenylalanine (C 11 H 13 NO 5 ): changes in medium composition, pH of production medium, various growth phases of seed culture, amino acid supplementation and addition of anion exchange resin to the submerged culture. Biological activities of secondary metabolites were examined with the use of dd-carboxypeptidase 64-575 and horseradish peroxidase. Streptomyces sp. 8812 mycelium was evaluated under fluorescent microscopy and respiratory activity of the strain was analyzed. Moreover, the enzymatic profiles of the strain with the use of Api®ZYM test were analyzed and genetic analysis made. Phylogenetic analysis of Strepto myces sp. 8812 revealed that its closest relative is Streptomyces capoamus JCM 4734 (98%), whereas sequence analysis for 16S rRNA gene using NCBI BLAST algorithm showed 100% homology between these two strains. Biosynthetic processes, mycelium growth and enzyme inhibitory activities of these two strains were also compared.K e y w o r d s: Streptomyces sp. 8812, biologically active compounds, media optimization, submerged cultures

Natural medicinal resources are a country’s natural wealth. Natural medicinal waters, medicinal gases, and peloids have many properties that enable their use in the treatment of gastrointestinal, circulatory, respiratory, bone and joint, and skin and soft tissue disorders. Balneotherapy can be also applicable in prevention of many diseases and rehabilitation. At present, because there are several chemicals of synthetic origin, there is a need to search for nonpharmacological approaches and explore natural healing sources, which better fit the human body. Compared to synthetic drugs, these resources rarely show side effects, which increases the comfort of therapy. The use of natural medicinal resources in the form of treatments in health resort medicine centers under the supervision of balneologists, combined with the healing properties of the climate, contributes not only to the reduction of treatment time for many diseases but also to improvement of therapy’s results. The article discusses natural medicinal resources and some of their therapeutic applications.