Quercetin and its derivatives are important metabolites that belong to the flavonol class of flavonoids. Quercetin and some of the conjugates have been approved by the FDA for human use. They are widely distributed among plants and have various biological activities, such as being anticancer, antiviral, and antioxidant. Hence, the biosynthesis of novel derivatives is an important field of research. Glycosylation and methylation are two important modification strategies that have long been used and have resulted in many novel metabolites that are not present in natural sources. A strategy for modifying quercetin in E. coli by means of glycosylation, for example, involves overexpressing respective glycosyltransferases (GTs) in the host and metabolic engineering for increasing nucleoside diphosphate sugar (NDP sugar). Still others have used microorganisms other than E. coli, such as Streptomyces sp., for the biotransformation process. The overall study of the structural activity relationship has revealed that modification of some residues in quercetin decreased one activity but increased others. This review summarizes all of the information mentioned above.

Streptomyces are well-known for producing bioactive secondary metabolites, with numerous antimicrobials essential to fight against infectious diseases. Globally, multidrug-resistant (MDR) microorganisms significantly challenge human and veterinary diseases. To tackle this issue, there is an urgent need for alternative antimicrobials. In the search for potent agents, we have isolated four Streptomyces species PC1, BT1, BT2, and BT3 from soils collected from various geographical regions of the Himalayan country Nepal, which were then identified based on morphology and 16S rRNA gene sequencing. The relationship of soil microbes with different Streptomyces species has been shown in phylogenetic trees. Antimicrobial potency of isolates was carried out against Staphylococcus aureus American Type Culture Collection (ATCC) 43300, Shigella sonnei ATCC 25931, Salmonella typhi ATCC 14028, Klebsiella pneumoniae ATCC 700603, and Escherichia coli ATCC 25922. Among them, Streptomyces species PC1 showed the highest zone of inhibition against tested pathogens. Furthermore, ethyl acetate extracts of shake flask fermentation of these Streptomyces strains were subjected to liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis for their metabolic comparison and Global Natural Products Social Molecular Networking (GNPS) web-based molecular networking. We found very similar metabolite composition in four strains, despite their geographical variation. In addition, we have identified thirty-seven metabolites using LC-MS/MS analysis, with the majority belonging to the diketopiperazine class. Among these, to the best of our knowledge, four metabolites, namely cyclo-(Ile-Ser), 2-n-hexyl-5-n-propylresorcinol, 3-[(6-methylpyrazin-2-yl) methyl]-1H-indole, and cyclo-(d-Leu-l-Trp), were detected for the first time in Streptomyces species. Besides these, other 23 metabolites including surfactin B, surfactin C, surfactin D, and valinomycin were identified with the help of GNPS-based molecular networking.

Anthraquinone and its derivatives show remarkable biological properties such as anticancer, antibacterial, antifungal, and antiviral activities. Hence, anthraquinones derivatives have been of prime interest in drug development. This study developed a recombinant Escherichia coli strain to modify chrysazin to chrysazin-8-O-α-l-rhamnoside (CR) and chrysazin-8-O-α-l-2′-O-methylrhamnoside (CRM) using rhamnosyl transferase and sugar-O-methyltransferase. Biosynthesized CR and CRM were structurally characterized using HPLC, high-resolution mass spectrometry, and various nuclear magnetic resonance analyses. Antimicrobial effects of chrysazin, CR, and CRM against 18 superbugs, including 14 Gram-positive and 4 Gram-negative pathogens, were investigated. CR and CRM exhibited antimicrobial activities against nine pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) in a disk diffusion assay at a concentration of 40 µg per disk. There were MIC and MBC values of 7.81–31.25 µg/mL for CR and CRM against methicillin-sensitive S. aureus CCARM 0205 (MSSA) for which the parent chrysazin is more than >1000 µg/mL. Furthermore, the anti-proliferative properties of chrysazin, CR, and CRM were assayed using AGS, Huh7, HL60, and HaCaT cell lines. CR and CRM showed higher antibacterial and anticancer properties than chrysazin.

The identification of specialized metabolites isolated from microorganisms is urgently needed to determine their roles in treating cancer and controlling multidrug-resistant pathogens. Naphthoquinones act as anticancer agents in various types of cancers, but some toxicity indicators have been limited in their appropriate application. In this context, new isofuranonaphthoquinones (ifnq) that are less toxic to humans could be promising lead compounds for developing anticancer drugs. The aim of this study is to identify and characterize novel furanonaphthoquinones (fnqs) from Nocardia sp. CS682 and to evaluate their potential therapeutic applications. Analysis of the genome of Nocardia sp. CS682 revealed the presence of a furanonaphthoquinone (fnq) gene cluster, which displays a similar genetic organization and high nucleotide sequence identity to the ifnq gene cluster from Streptomyces sp. RI-77, a producer of the naphthoquinones JBIR-76 and JBIR-77. In this study, the overexpression of the Streptomyces antibiotic regulatory protein (SARP) in Nocardia sp. CS682DR (nargenicin gene-deleted mutant) explicitly produced new fnqs, namely, NOC-IBR1 and NOC-IBR2. Subsequently, the role of the SARP regulator was confirmed by gene inactivation using CRISPR-Cas9 and complementation studies. Furthermore, antioxidant, antimicrobial, and cytotoxicity assays were performed for the isolated compounds, and it was found that NOC-IBR2 exhibited superior activities to NOC-IBR1. In addition, a flexible methyltransferase substrate, ThnM3, was found to be involved in terminal methylation of NOC-IBR1, which was confirmed by in vitro enzyme assays. Thus, this study supports the importance of genome mining and genome editing approaches for exploring new specialized metabolites in a rare actinomycete called Nocardia.

Metabolic profiling of actinomycetes isolated from Nepalese soil has uncovered promising candidates for the development of new antimicrobial and anticancer agents. This research examines the potential of actinobacteria isolated from soil, namely strains PY40, PY118, and PY122, as promising sources for biological applications. These strains were identified using 16S rRNA gene sequencing as Streptomyces sp. PY40, Streptomyces sp. PY118, and Amycolatopsis sp. PY122. Comprehensive bioassays were carried out on ethyl acetate (EA) extract originating from the fermentation broths of these species to assess their antimicrobial and anticancer activities. The results showed noteworthy antifungal and anticancer properties of Streptomyces sp. PY40 extract, thereby indicating its possible use in the synthesis of pharmaceuticals. Furthermore, potent antifungal activity was observed with an extract from Amycolatopsis sp. PY122. These isolates showed strong inhibition against several multi-drug-resistant strains of bacteria, including Shigella sonnei ATCC 25931, Klebsiella pneumoniae ATCC 700603, Escherichia coli ATCC 25922, and, Staphylococcus aureus ATCC 43300, suggesting significant antibacterial activity of the extracts. Gas Choursomatography-Mass Spectrometry (GC-MS) analysis revealed particularly volatile chemical constituents in the extracts. Antibiotic agents such as diketopiperazines and hexahydropyrrolo[1,2-a]pyrazine-1,4-dione were prevalent in the extracts of these isolates. This study enhances our comprehension of the bioactive potential of these microorganisms and underscores their value as a source for creating novel therapeutics to address multi-resistant infections and cancer demands. These findings show that actinomycetes from Nepalese soil have high prospects for biological applications.