Secondary Metabolites of Actinomycetes and their Antibacterial, Antifungal and Antiviral Properties.

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.

Cyclo(Pro-DOPA), a third identified bioactive metabolite produced by Streptomyces sp. 8812.

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.

Cymantrenyl-Nucleobases: Synthesis, Anticancer, Antitrypanosomal and Antimicrobial Activity Studies.

The synthesis of four cymantrene-5-fluorouracil derivatives (1-4) and two cymantrene-adenine derivatives (5 and 6) is reported. All of the compounds were characterized by spectroscopic methods and the crystal structure of two derivatives (1 and 6), together with the previously described cymantrene-adenine compound C was determined by X-ray crystallography. While the compounds 1 and 6 crystallized in the triclinic P-1 space group, compound C crystallized in the monoclinic P21/m space group. The newly synthesized compounds 1-6 were tested together with the two previously described cymantrene derivatives B and C for their in vitro antiproliferative activity against seven cancer cell lines (MCF-7, MCF-7/DX, MDA-MB-231, SKOV-3, A549, HepG2m and U-87-MG), five bacterial strains Staphylococcus aureus (methicillin-sensitive, methicillin-resistant and vancomycin-intermediate strains), Staphylococcus epidermidis, and Escherichia coli, including clinical isolates of S. aureus and S. epidermidis, as well as against the protozoan parasite Trypanosoma brucei. The most cytotoxic compounds were derivatives 2 and C for A549 and SKOV-3 cancer cell lines, respectively, with 50% growth inhibition (IC50) values of about 7 µM. The anticancer activity of the cymantrene compounds was determined to be due to their ability to induce oxidative stress and to trigger apoptosis and autophagy in cancer cells. Three derivatives (1, 4 and 5) displayed promising antitrypanosomal activity, with GI50 values in the low micromolar range (3-4 µM). The introduction of the 5-fluorouracil moiety in 1 enhanced the trypanocidal activity when compared to the activity previously reported for the corresponding uracil derivative. The antibacterial activity of cymantrene compounds 1 and C was within the range of 8-64 µg/mL and seemed to be the result of induced cell shrinking.