Anulamycins A-F, Cinnamoyl-Containing Peptides from a Lake Sediment Derived Streptomyces.

Bioinformatics analysis of a whole genome sequence coupled with HPLC-DAD analysis revealed that Streptomyces sp. Hu103 has the capacity to produce skyllamycin analogues. A subsequent chemical investigation of this strain yielded four new cinnamoyl-containing cyclopeptides, anulamycins A-D (1-4), two new cinnamoyl-containing linear peptides, anulamycins E and F (5 and 6), and two known cyclopeptides, skyllamycins A (7) and B (8). Their structures including absolute configurations were elucidated by detailed analysis of NMR and HRESIMS/MS spectroscopic data and the advanced Marfey's method. Compounds 1-4 exhibited antibacterial activity comparable to those of skyllamycins A and B.

Repurposing Salicylamides to Combat Phytopathogenic Bacteria and Induce Plant Defense Responses.

Based on the research strategy of "drug repurposing", a series of derivatives and marketed drugs that containing salicylic acid skeleton were tested for their antibacterial activities against phytopathogens. Salicylic acid can not only regulate some important growth metabolism of plants, but also induce plant disease resistance. The bioassay results showed that the salicylamides exhibited excellent antibacterial activity. Especially, oxyclozanide showed the best antibacterial effect against Xanthomonas oryzae, Xanthomonas axonopodis pv. citri and Pectobacterium atroseptica with MICs of 0.78, 3.12 and 12.5 µg.mL-1, respectively. In vivo experiments with rice bacterial leaf blight had further demonstrated that oxyclozanide exhibited stronger antibacterial activity than the commercial bactericide, thiodiazole copper. Oxyclozanide could induce plant defense responses through the determination of salicylic acid content and the activities of defense-related enzymes including CAT, POD, and SOD in rice. The preliminarily antibacterial mechanism study indicated that oxyclozanide exhibited the antibacterial activity by disrupting cell integrity and reducing bacterial pathogenicity. Additionally, oxyclozanide could induce plant defense responses through the determination of salicylic acid content.

Sarubicinols A-C, Cytotoxic Benzoxazoles from a Streptomyces.

A chemical investigation of Streptomyces sp. Hu186 afforded two known quinone antibiotics, sarubicin A (1) and sarubicin B (2), together with three unusual variants, sarubicinols A-C (3-5), and two new 1,4-naphthoquinone metabolites, sarubicin B1 (6) and sarubicin B2 (7). Compounds 3-5 possess a rare 2-oxabicyclo [2.2.2] substructure and a benzoxazole ring system. Their structures were elucidated using 1D and 2D nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry data. The absolute configurations of the side-chain moieties in 4 and 5 were solved by electronic circular dichroism calculations. Compounds 1-7 showed moderate cytotoxic activity against four tumor cell lines.

Antibacterial activity and action mechanism of flavonoids against phytopathogenic bacteria.

As the most difficult to control in plant disease, phytopathogenic bacteria cause huge losses to agricultural products and economy worldwide. However, the commercially available bactericides are few and enhance pathogen resistance. To alleviate this situation, 50 flavonoids were evaluated for their antibacterial activities and mechanism of action against two intractable plant bacterial pathogens. The results of bioassays showed that most of the flavonoids exhibited moderate inhibitory effects against Xanthomonas oryzae (Xo) and Xanthomonas axonopodis pv citri (Xac). Remarkably, kaempferol showed excellent antibacterial activity against Xo in vitro (EC50 = 15.91 µg/mL) and quercetin showed the best antibacterial activity against Xac in vitro (EC50 = 14.83 µg/mL), which was better than thiodiazole copper (EC50 values against Xo and Xac were 16.79 µg/mL, 59.13 µg/mL, respectively). Subsequently, in vivo antibacterial activity assay further demonstrated kaempferol exhibited a stronger control effect on bacterial infections than thiodiazole copper. Then, the preliminary antibacterial mechanism of kaempferol was investigated by ultrastructural observations, transcriptomic, qRT-PCR analysis and biochemical index determination. These results showed that kaempferol mainly exerted bacteriostatic effects at the molecular level by affecting bacterial energy metabolism, reducing pathogenicity, and leading to disruption of cellular integrity, leakage of contents and cell death eventually.

Two new cyclopentenone metabolites from Streptomyces sp. HU119.

Two previously undescribed cyclopentenone metabolites, (S)-2-(3-acetylamino-2-methyl)propyl-3-butyl-2-cyclopenten-1-one (1) and (S)-2-(3-acetylamino-2-ethyl)propyl-3-butyl-2-cyclopenten-1-one (2), were isolated from the fermentation broth of the strain Streptomyces sp. HU119. The structures of 1 and 2 were determined by the comprehensive spectroscopic analysis, including 1 D, 2 D NMR, MS spectral analysis and the comparison with data from the literature. The absolute configurations were elucidated by experimental and calculated optical rotations (OR). Compounds 1 and 2 displayed weak cytotoxic activity.

Two new 13-hydroxylated milbemycin metabolites from the genetically engineered strain Streptomyces avermitilis AVE-H39.

Two new milbemycin metabolites, 13α-hydroxymilbemycin ß13 (1) and 26-methyl-13α-hydroxymilbemycin ß13 (2), were isolated from the fermentation broth of a genetically engineered strain Streptomyces avermitilis AVE-H39. Their structures were determined by the comprehensive spectroscopic data, including 1 D, 2 D NMR, MS spectral analysis and the comparison with data from the literature. Compounds 1 and 2 not only exhibited potent acaricidal activities against Tetranychus cinnabarinus, but also had nematocidal activity against Bursaphelenchus xylophilus.

Two new milbemycin derivatives from a genetically engineered strain Streptomyces bingchenggensis.

Two new milbemycin derivatives, milbemycin M (1) and milbemycin N (2), were isolated from the culture of a genetically engineered strain Streptomyces bingchenggensis BCJ60. Their structures were elucidated through the interpretation of NMR and HR-ESI-MS spectroscopic data, as well as comparison with previous reports. The acaricidal and nematicidal activities of them against Tetranychus cinnabarinus and Bursaphelenchus xylophilus were tested. The results showed that compounds 1-2 possessed potent acaricidal and nematocidal activities.

Three New Isoflavonoid Glycosides from the Mangrove-Derived Actinomycete Micromonospora aurantiaca 110B.

The mangrove ecosystem is a rich resource for the discovery of actinomycetes with potential applications in pharmaceutical science. Besides the genus Streptomyces, Micromonospora is also a source of new bioactive agents. We screened Micromonospora from the rhizosphere soil of mangrove plants in Fujian province, China, and 51 strains were obtained. Among them, the extracts of 12 isolates inhibited the growth of human lung carcinoma A549 cells. Strain 110B exhibited better cytotoxic activity, and its bioactive constituents were investigated. Consequently, three new isoflavonoid glycosides, daidzein-4'-(2-deoxy-α-l-fucopyranoside) (1), daidzein-7-(2-deoxy-α-l-fucopyranoside) (2), and daidzein-4',7-di-(2-deoxy-α-l-fucopyranoside) (3) were isolated from the fermentation broth of strain 110B. The structures of the new compounds were determined by spectroscopic methods, including 1D and 2D nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HR-ESIMS). The result of medium-changing experiments implicated that these new compounds were microbial biotransformation products of strain M. aurantiaca 110B. The three compounds displayed moderate cytotoxic activity to the human lung carcinoma cell line A549, hepatocellular liver carcinoma cell line HepG2, and the human colon tumor cell line HCT116, whereas none of them showed antifungal or antibacterial activities.

Two new tenvermectins from a genetically engineered strain Streptomyces avermitilis MHJ1011.

Two new tenvermectins, tenvermectins C (1) and D (2), were isolated from Streptomyces avermitilis MHJ1011. Their structures were determined by extensive spectroscopic analysis and by comparison with a related known compound, tenvermectin A. Compounds 1 and 2 exhibited potent nematocidal and acaricidal activities against Bursaphelenchus xylophilus and Tetranychus cinnabarinus.

New macrocyclic lactones with acaricidal and nematocidal activities from a genetically engineered strain Streptomyces bingchenggensis BCJ60.

Two new macrocyclic lactones, 4,25-diethyl-4,25-demethyl-milbemycin ß3 (1) and 27-formaldehyde-milbemycin ß14 (2), were isolated from a genetically engineered strain Streptomyces bingchenggensis BCJ60. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. The acaricidal and nematocidal capacities of compounds 1 and 2 were evaluated against Tetranychus cinnabarinus and Bursaphelenchus xylophilus, respectively. The results showed that the two new macrocyclic lactones 1 and 2 possessed potent acaricidal and nematocidal activities.

Three new 16-membered macrolide compounds from a genetically engineered strain S. avermitilis MHJ1011.

Three new 16-membered macrolide compounds, 13α-O-α-l-oleandrosyl milbemycin ß3 (1), 13α-O-α-l-oleandrosyl-25-ethyl milbemycin ß3 (2), 13α-O-α-l-oleandrosyl-25-isopropyl milbemycin ß3 (3), were isolated from the genetically engineered strains Streptomyces avermitilis MHJ1011. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. Both compounds 1-3 displayed impressive acaricidal activity against larval mites with the IC50 values of 0.0327, 0.0276 and 0.0235mg/L, respectively, which are higher than those of 13α-hydroxy milbemycin ß3 and 13α-hydroxy-25-ethyl milbemycin ß3.

Perspectives on biologically active camptothecin derivatives.

Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small-molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.

Synthesis, biological activities, and quantitative structure-activity relationship (QSAR) study of novel camptothecin analogues.

In continuation of our program aimed at the development of natural product-based pesticidal agents, three series of novel camptothecin derivatives were designed, synthesized, and evaluated for their biological activities against T. Cinnabarinus, B. brassicae, and B. xylophilus. All of the derivatives showed good-to-excellent activity against three insect species tested, with LC50 values ranging from 0.00761 to 0.35496 mmol/L. Remarkably, all of the compounds were more potent than CPT against T. Cinnabarinus, and compounds 4d and 4c displayed superior activity (LC50 0.00761 mmol/L and 0.00942 mmol/L, respectively) compared with CPT (LC50 0.19719 mmol/L) against T. Cinnabarinus. Based on the observed bioactivities, preliminary structure-activity relationship (SAR) correlations were also discussed. Furthermore, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) was built. The model gave statistically significant results with the cross-validated q2 values of 0.580 and correlation coefficient r2 of 0.991 and  of 0.993. The QSAR analysis indicated that the size of the substituents play an important in the activity of 7-modified camptothecin derivatives. These findings will pave the way for further design, structural optimization, and development of camptothecin-derived compounds as pesticidal agents.

Two new aromatic tenvermectins from mutant Streptomyces avermitilis HU02-06.

Two new aromatic tenvermectins (TVMs), 13-oleandrosyl-oleandrosyloxy ST906 (1) and aromatic TVM B (2), were isolated from the fermentation broth of Streptomyces avermitilis HU02-06. Their structures were established by extensive spectroscopic analysis, including 1D and 2D NMR and HRESIMS data. Bioassay test showed that these two new tenvermectins exhibited weak nematocidal activity against Bursaphelenchus xylophilus and moderate cytotoxic activity against tumor cell lines HepG2 and HCT116.

Antifungal Activity and Putative Mechanism of HWY-289, a Semisynthetic Protoberberine Derivative, against Botrytis cinerea.

The emergence of resistant pathogens has increased the demand for alternative fungicides. The use of natural products as chemical scaffolds is a potential method for developing fungicides. HWY-289, a semisynthetic protoberberine derivative, demonstrated broad-spectrum and potent activities against phytopathogenic fungi, particularly Botrytis cinerea (with EC50 values of 1.34 µg/mL). SEM and TEM imaging indicated that HWY-289 altered the morphology of the mycelium and the internal structure of cells. Transcriptomics revealed that it could break down cellular walls through amino acid sugar and nucleotide sugar metabolism. In addition, it substantially decreased chitinase activity and chitin synthase gene (BcCHSV) expression by 53.03 and 82.18% at 1.5 µg/mL, respectively. Moreover, this impacted the permeability and integrity of cell membranes. Finally, HWY-289 also hindered energy metabolism, resulting in a significant reduction of ATP content, ATPase activities, and key enzyme activities in the TCA cycle. Therefore, HWY-289 may be a potential candidate for the development of plant fungicides.

Confirmation of the absolute configuration of tenvermectin B by single-crystal X-ray diffraction analysis of its furan formate derivative.

Tenvermectins A and B are a kind of 16-membered macrocyclic lactone antibiotics with potent insecticidal property, which have been obtained from two genetically engineered strains Streptomyces avermitilis MHJ1011 and S. avermitilis AVE-H39. Aiming at confirming the absolute configuration of tenvermectin B by X-ray diffraction method, 4″, 5 -di-(2-furoyloxyl) tenvermectin B (1) was prepared and a suitable crystal of 1 was obtained from MeOH. The absolute configuration of 1 was unambiguously established by single-crystal X-ray diffraction analysis. The determination of the stereochemistry of tenvermectin B could promote its chemical and biological studies as agricultural and veterinary agents. In addition, compound 1 displayed weak acaricidal and nematocidal activities against Tetranychus cinnabarinus and Bursaphelenchus xylophilus respectively.

A new ß-class milbemycin derivative from a mutant of genetically engineered strain Streptomyces avermitilis AVE-H39.

A new ß-class milbemycin, 13α-hydroxy milbemycin ß6 (1), was isolated from the fermentation broth of a mutant of genetically engineered strain Streptomyces avermitilis AVE-H39. Its structure and absolute configuration were elucidated by extensive spectroscopic methods and confirmed by single crystal X-ray diffraction.

A novel spiro-heterocycle milbemycin metabolite from a genetically engineered strain of Streptomyces bingchenggensis.

Milbemycin R, a novel spiro-heterocycle milbemycin, was obtained from the metabolites produced by the mutant strain S. bingchenggensis BCJ60B11. Its structure was determined by spectroscopic and spectrometric analyses including 1 D, 2 D NMR, IR, HR-ESI-MS data. The acaricidal and nematicidal activities of milbemycin R against Tetranychus cinnabarinus and Bursaphelenchus xylophilus were tested. Milbemycin R possessed better acaricidal activity than milbemycins A3/A4.

Antimicrobial activity of natural and semi-synthetic carbazole alkaloids.

Since the first natural carbazole alkaloid, murrayanine, was isolated from Mwraya Spreng, carbazole alkaloid derivatives have been widely concerned for their anti-tumor, anti-viral and anti-bacterial activities. In recent decades, a growing body of data suggest that carbazole alkaloids and their derivatives have different biological activities. This is the first comprehensive description of the antifungal and antibacterial activities of carbazole alkaloids in the past decade (2012-2022), including natural and partially synthesized carbazole alkaloids in the past decade. Finally, the challenges and problems faced by this kind of alkaloids are summarized. This paper will be helpful for further exploration of this kind of alkaloids.

Exploring boron applications in modern agriculture: Antifungal activities and mechanisms of phenylboronic acid derivatives.

BACKGROUND: The unreasonable use of chemical fungicides causes common adverse consequences that not only affect the environment, but also cause resistance and resurgence problems of plant pathogens, which are extremely harmful to human health, the economy, and the environment. Based on the rich biological activities of boron-based compounds, 82 phenylboronic acid derivatives were selected and their antifungal activities against six agricultural plant pathogens were determined. Combined with transcriptomics tools, the mechanism of action of compound A49 (2-chloro-5-trifluoromethoxybenzeneboronic acid) against Botrytis cinerea Pers (B. cinerea) was studied. RESULTS: The EC50 values of compounds A24, A25, A30, A31, A36, A41, A49 and B23 against all six fungi were under 10 µg/mL. Compound A49 displayed significant activity against B. cinerea (EC50 = 0.39 µg/mL), which was better than that of commercial fungicide boscalid (EC50 = 0.55 µg/mL). A49 not only inhibited the germination of B. cinerea spores, but also caused abnormal cell morphology, loss of cell membrane integrity, enhanced cell membrane permeability, and accumulation of intracellular reactive oxygen species. Further findings showed that A49 reduced cellular antioxidant activity, and peroxidase and catalase activities. Transcriptomic results indicated that A49 could degrade intracellular redox processes and alter the metabolism of some amino acids. Meanwhile, A49 showed obvious activity in vivo and low cytotoxicity to mammal cells. CONCLUSION: The boron-containing small molecule compounds had high efficiency and broad-spectrum antifungal activities against six plant pathogens, and are expected to be candidate compounds for a new class of antifungal drugs. © 2023 Society of Chemical Industry.