The emergence of communicable and non-communicable diseases has posed a health challenge for millions of people worldwide and is a major threat to the economic and social development in the coming century. The occurrence of the recent pandemic, SARS-CoV-2, caused by lethal severe acute respiratory syndrome coronavirus 2, is one such example. Rapid research and development of drugs for the treatment and management of these diseases have become an incredibly challenging task for the pharmaceutical industry. Although, substantial attention has been paid to the discovery of therapeutic compounds from natural sources having significant medicinal potential, their synthesis has made a slow progress. Hence, the discovery of new targets by the application of the latest biotechnological and synthetic biology approaches is very much the need of the hour. Polyketides (PKs) and non-ribosomal peptides (NRPs) found in bacteria, fungi and plants are a diverse family of natural products synthesized by two classes of enzymes: polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS). These enzymes possess immense biomedical potential due to their simple architecture, catalytic capacity, as well as diversity. With the advent of the latest in-silico and in-vitro strategies, these enzymes and their related metabolic pathways, if targeted, can contribute highly towards the biosynthesis of an array of potentially natural drug leads that have antagonist effects on biopolymers associated with various human diseases. In the face of the rising threat from multidrug-resistant pathogens, this will further open new avenues for the discovery of novel and improved drugs by combining natural and synthetic approaches. This review discusses the relevance of polyketides and non-ribosomal peptides and the improvement strategies for the development of their derivatives and scaffolds, and how they will be beneficial for future bioprospecting and drug discovery.
Some aromatic polyketides such as dietary flavonoids have gained reputation as miraculous molecules with preeminent beneficial effects on human health, for example, as antioxidants. However, there is little conclusive evidence that dietary flavonoids provide significant leads for developing more effective drugs, as the majority appears to be of negligible medicinal importance. Some aromatic polyketides of limited distribution have shown more interesting medicinal properties and additional research should be focused on them. Combretastatins, analogues of phenoxodiol, hepatoactive kavalactones, and silymarin are showing a considerable promise in the advanced phases of clinical trials for the treatment of various pathologies. If their limitations such as adverse side effects, poor water solubility, and oral inactivity are successfully eliminated, they might be prime candidates for the development of more effective and in some case safer drugs. This review highlights some of the newer compounds, where they are in the new drug pipeline and how researchers are searching for additional likely candidates.
- MeSH
- antioxidancia * chemie terapeutické užití MeSH
- flavonoidy * chemie terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- polyketidy * chemie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The open-source and cross-platform software CycloBranch was utilized for dereplication of organic compounds from mass spectrometry imaging imzML datasets and its functions were illustrated on microbial siderophores. The pixel-to-pixel batch-processing was analogous to liquid chromatography mass spectrometry data. Each data point represented here by accurate m/z values and the corresponding ion intensities was matched against integrated compound libraries. The fine isotopic structure matching was also embedded into CycloBranch dereplication process. The siderophores' characterization from single-pixel mass spectra was further supported by their de novo sequencing. New ketide building block library was utilized by CycloBranch to characterize the siderophores in images and mixtures and nomenclature of fragment ion series of linear and cyclic polyketide siderophores was proposed. The software is freely available at http://ms.biomed.cas.cz/cyclobranch. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.
Myxobacteria, a group of antimicrobial producing bacteria, have been successfully cultured and characterized from ten soil samples collected from different parts of Slovakia. A total of 79 myxobacteria belonging to four genera (Myxococcus, Corallococcus, Sorangium, and Polyangium) were isolated based on aspects of their life cycle. Twenty-five of them were purified, fermented, and screened for antimicrobial activities against 11 test microorganisms. Results indicated that crude extracts showed more significant activities against Gram-positive than against Gram-negative bacteria or fungi. Based on a higher degree and broader range of antimicrobial production, the two most potential extracts (K9-5, V3-1) were selected for HPLC fractionation against Micrococcus luteus and Staphylococcus aureus and LC/MS analysis of potential antibiotic metabolites. The analysis resulted in the identification of polyketide-peptide antibiotics, namely corallopyronin A and B (K9-5) and myxalamid B and C (V3-1), which were responsible for important Gram-positive activity in the observed strains. A sequence similarity search through BLAST revealed that these strains showed the highest sequence similarity to Corallococcus coralloides (K9-5, NCBI accession number KX256198) and Myxococcus xanthus (V3-1, NCBI accession number KX256197). Although screening of myxobacteria is laborious, due to difficulties in isolating cultures, this research represented the first report covering the isolation and cultivation of this challenging bacterial group from Slovakian soils as well as the screening of their antimicrobial activity, cultural identification, and secondary metabolite identification.
- MeSH
- antibakteriální látky chemie metabolismus farmakologie MeSH
- fylogeneze MeSH
- Micrococcus luteus účinky léků MeSH
- Myxococcales chemie genetika izolace a purifikace metabolismus MeSH
- polyketidy chemie metabolismus farmakologie MeSH
- půdní mikrobiologie * MeSH
- Staphylococcus aureus účinky léků MeSH
- Publikační typ
- časopisecké články MeSH
Manumycinová antibiotika jsou malou skupinou polyketidových látek, které se navzájem podobají svojí strukturou a vykazují výrazné antimikrobiální, protizánětlivé či protinádorové aktivity. Prozatím bohužel nebyl zcela prozkoumán vztah jednotlivých struktur molekul k těmto biologickým aktivitám ani nebyla popsána biosyntetická dráha většiny z těchto látek. Další výzkum v těchto oblastech by mohl v budoucnu vést k praktickému využití manumycinových antibiotik např. v lékařství.
Manumycin antibiotics represent small group of polyketide metabolites. They have similar structure and possess significant antimicrobial, anti-inflammatory or antitumor activities. To date, relationships of structure and biological activities have not been fully investigated. Also biosynthetic pathways of most manumycins are still not clear. Their further research could lead to application of manumycins e.g. in human medicine.
- MeSH
- antibakteriální látky * biosyntéza farmakokinetika chemie klasifikace MeSH
- farnesyltranstransferasa antagonisté a inhibitory biosyntéza farmakologie chemie MeSH
- grampozitivní bakteriální infekce farmakoterapie MeSH
- lidé MeSH
- polyketidy * farmakologie chemie MeSH
- polynenasycené alkamidy farmakologie chemie MeSH
- protinádorové látky * farmakologie chemie MeSH
- Streptomyces MeSH
- Check Tag
- lidé MeSH
Resorcylic acid lactones (RALs) are polyketide natural products with a large macrocyclic ring fused to a resorcylic acid residue. Some RALs contain an α,β-unsaturated ketone in the macrocycle. So far 46 kinases have been identified that could be potentially targeted by this family of compounds. RALs are of interest for their modulation of growth, and tentatively for the treatment of cancer and neurodegenerative diseases. RALs containing a cis-enone are susceptible to Michael addition reactions with the cysteine residue in the kinase nucleotide binding site, and thus serve as potent inhibitors of several protein kinases - they therefore represent a unique pharmacophore. Notably, this moiety has been shown to be effective also in vivo. This mini-review focuses on the structure and biological effects of the most important RALs, namely zearalenone, hypothemycin, pochonins, lasiodiplodins, aigialomycins, cochlicomycins, zaenols, and paecilomycins. Finally, the review also deals with radicicol, which is a nanomolar inhibitor of the chaperone Hsp90, whose suppression leads to a combinatorial block of cancer-causing pathways.
- MeSH
- biologické přípravky chemie farmakologie MeSH
- inhibitory proteinkinas chemie farmakologie MeSH
- lidé MeSH
- mykotoxiny chemie farmakologie MeSH
- polyketidy chemie farmakologie MeSH
- proteinkinasy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
