scholarly journals New from old: discovery of the novel antibiotic actinomycin L in Streptomyces sp. MBT27

2021 ◽  
Author(s):  
Nataliia Machushynets ◽  
Somayah S. Elsayed ◽  
Chao Du ◽  
Maxime A. Siegler ◽  
Mercedes de la Cruz ◽  
...  
Keyword(s):  
Natural Products ◽  
Metabolic Pathways ◽  
Chemical Space ◽  
Carbon Sources ◽  
Growth Conditions ◽  
Biosynthetic Gene Cluster ◽  
The Novel ◽  
Product Families ◽  
Antibiotic Discovery ◽  
The Impact

ABSTRACTStreptomycetes are major producers of bioactive natural products, including the majority of the antibiotics. While much if the low-hanging fruit has been discovered, it is predited that less than 5% of the chemical space has been mined. Here, we describe the novel actinomycins L1 and L2, which are produced by Streptomyces sp. MBT27. The molecules were discovered via metabolic analysis combined with molecular networking of cultures grown with different combinations of carbon sources. Actinomycins L1 and L2 are diastereoisomers, and the structure of actinomycin L2 was resolved using NMR and single crystal X-ray crystallography. Actinomycin L is formed via a unique spirolinkage of anthranilamide to the 4-oxoproline moiety of actinomycin X2, prior to the condensation of the actinomycin halves. Feeding anthranilamide to cultures of Streptomyces antibioticus, which has the same biosynthetic gene cluster as Streptomyces sp. MBT27 but only produces actinomycin X2, resulted in the production of actinomycin L. This shows that actinomycin L results from joining two distinct metabolic pathways, namely those for actinomycin X2 and for anthranilamide. Actinomycins L1 and L2 showed significant antimicrobial activity against Gram- positive bacteria. Our work shows how new molecules can still be identified even in the oldest of natural product families.IMPORTANCEActinomycin was the first antibiotic discovered in an actinobacterium by Selman Waksman and colleagues, as early as 1940. This period essentially marks the start of the ‘golden era’ of antibiotic discovery. Over time, emerging antimicrobial resistance (AMR) and the declining success rate of antibiotic discovery resulted in the current antibiotic crisis. We surprisingly discovered that under some growth conditions, Streptomyces sp. MBT27 can produce actinomycins that are significantly different from those that have been published so far. The impact of this work is not only that we have discovered a novel molecule with very interesting chemical modifications in one of the oldest antibiotics ever described, but also that this requires the combined action of primary and secondary metabolic pathways, namely the biosynthesis of anthranilamide and of actinomycin X2, respectively. The implication of the discovery is that even the most well-studied families of natural products may still have surprises in store for us.

scholarly journals Biosynthetic Potential of a Novel Antarctic Actinobacterium Marisediminicola antarctica ZS314T Revealed by Genomic Data Mining and Pigment Characterization

Marine Drugs ◽  
2019 ◽  
Vol 17 (7) ◽  
pp. 388 ◽  
Author(s):  
Li Liao ◽  
Shiyuan Su ◽  
Bin Zhao ◽  
Chengqi Fan ◽  
Jin Zhang ◽  
...  
Keyword(s):  
Data Mining ◽  
Natural Products ◽  
Gene Cluster ◽  
Genomic Data ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
The Novel ◽  
Biosynthetic Gene ◽  
Base Pairs ◽  
Peptide Synthetase

Rare actinobacterial species are considered as potential resources of new natural products. Marisediminicola antarctica ZS314T is the only type strain of the novel actinobacterial genus Marisediminicola isolated from intertidal sediments in East Antarctica. The strain ZS314T was able to produce reddish orange pigments at low temperatures, showing characteristics of carotenoids. To understand the biosynthetic potential of this strain, the genome was completely sequenced for data mining. The complete genome had 3,352,609 base pairs (bp), much smaller than most genomes of actinomycetes. Five biosynthetic gene clusters (BGCs) were predicted in the genome, including a gene cluster responsible for the biosynthesis of C50 carotenoid, and four additional BGCs of unknown oligosaccharide, salinixanthin, alkylresorcinol derivatives, and NRPS (non-ribosomal peptide synthetase) or amino acid-derived compounds. Further experimental characterization indicated that the strain may produce C.p.450-like carotenoids, supporting the genomic data analysis. A new xanthorhodopsin gene was discovered along with the analysis of the salinixanthin biosynthetic gene cluster. Since little is known about this genus, this work improves our understanding of its biosynthetic potential and provides opportunities for further investigation of natural products and strategies for adaptation to the extreme Antarctic environment.

scholarly journals Tumor Cells and Cancer-Associated Fibroblasts: An Updated Metabolic Perspective

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 399
Author(s):  
Géraldine Gentric ◽  
Fatima Mechta-Grigoriou
Keyword(s):  
Tumor Cells ◽  
Metabolic Pathways ◽  
Molecular Mechanisms ◽  
Carbon Sources ◽  
Cancer Associated Fibroblasts ◽  
The Past ◽  
Cancer Field ◽  
Metabolic Heterogeneity ◽  
The Impact ◽  
Shed Light

During the past decades, metabolism and redox imbalance have gained considerable attention in the cancer field. In addition to the well-known Warburg effect occurring in tumor cells, numerous other metabolic deregulations have now been reported. Indeed, metabolic reprograming in cancer is much more heterogeneous than initially thought. In particular, a high diversity of carbon sources used by tumor cells has now been shown to contribute to this metabolic heterogeneity in cancer. Moreover, the molecular mechanisms newly highlighted are multiple and shed light on novel actors. Furthermore, the impact of this metabolic heterogeneity on tumor microenvironment has also been an intense subject of research recently. Here, we will describe the new metabolic pathways newly uncovered in tumor cells. We will also have a particular focus on Cancer-Associated Fibroblasts (CAF), whose identity, function and metabolism have been recently under profound investigation. In that sense, we will discuss about the metabolic crosstalk between tumor cells and CAF.

scholarly journals Exploiting the Feedstock Flexibility of the Emergent Synthetic Biology Chassis Vibrio natriegens for Engineered Natural Product Production

Marine Drugs ◽  
2019 ◽  
Vol 17 (12) ◽  
pp. 679 ◽  
Author(s):  
Gregory A. Ellis ◽  
Tanya Tschirhart ◽  
Joseph Spangler ◽  
Scott A. Walper ◽  
Igor L. Medintz ◽  
...  
Keyword(s):  
Natural Products ◽  
Synthetic Biology ◽  
Biosynthetic Pathway ◽  
Carbon Sources ◽  
Beta Carotene ◽  
Biosynthetic Gene Cluster ◽  
Model Organisms ◽  
Rich Media ◽  
Vibrio Campbellii ◽  
Fast Growth Rate

A recent goal of synthetic biology has been to identify new chassis that provide benefits lacking in model organisms. Vibrio natriegens is a marine Gram-negative bacterium which is an emergent synthetic biology chassis with inherent benefits: An extremely fast growth rate, genetic tractability, and the ability to grow on a variety of carbon sources (“feedstock flexibility”). Given these inherent benefits, we sought to determine its potential to heterologously produce natural products, and chose beta-carotene and violacein as test cases. For beta-carotene production, we expressed the beta-carotene biosynthetic pathway from the sister marine bacterium Vibrio campbellii, as well as the mevalonate biosynthetic pathway from the Gram-positive bacterium Lactobacillus acidophilus to improve precursor abundance. Violacein was produced by expressing a biosynthetic gene cluster derived from Chromobacterium violaceum. Not only was V. natriegens able to heterologously produce these compounds in rich media, illustrating its promise as a new chassis for small molecule drug production, but it also did so in minimal media using a variety of feedstocks. The ability for V. natriegens to produce natural products with multiple industrially-relevant feedstocks argues for continued investigations into the production of more complex natural products in this chassis.

scholarly journals Strain Prioritization and Genome Mining for Enediyne Natural Products

mBio ◽  
2016 ◽  
Vol 7 (6) ◽  
Author(s):  
Xiaohui Yan ◽  
Huiming Ge ◽  
Tingting Huang ◽  
Hindra ◽  
Dong Yang ◽  
...  
Keyword(s):  
Natural Products ◽  
Cancer Cell ◽  
Polyketide Synthase ◽  
Chemical Space ◽  
Large Strain ◽  
Genome Mining ◽  
Biosynthetic Gene Cluster ◽  
Structural Features ◽  
A Genome ◽  
Strain Collection

ABSTRACT The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection. IMPORTANCE Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA-approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family.

scholarly journals Recapitulation of the evolution of biosynthetic gene clusters reveals hidden chemical diversity on bacterial genomes

2015 ◽  
Author(s):  
Pablo Cruz-Morales ◽  
Christian E. Martínez-Guerrero ◽  
Marco A. Morales-Escalante ◽  
Luis Yáñez-Guerra ◽  
Johannes Florian Kopp ◽  
...  
Keyword(s):  
Natural Products ◽  
Chemical Space ◽  
Streptomyces Coelicolor ◽  
Genome Mining ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Chemical Diversity ◽  
Biosynthetic Gene ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters

AbstractNatural products have provided humans with antibiotics for millennia. However, a decline in the pace of chemical discovery exerts pressure on human health as antibiotic resistance spreads. The empirical nature of current genome mining approaches used for natural products research limits the chemical space that is explored. By integration of evolutionary concepts related to emergence of metabolism, we have gained fundamental insights that are translated into an alternative genome mining approach, termed EvoMining. As the founding assumption of EvoMining is the evolution of enzymes, we solved two milestone problems revealing unprecedented conversions. First, we report the biosynthetic gene cluster of the ‘orphan’ metabolite leupeptin in Streptomyces roseus. Second, we discover an enzyme involved in formation of an arsenic-carbon bond in Streptomyces coelicolor and Streptomyces lividans. This work provides evidence that bacterial chemical repertoire is underexploited, as well as an approach to accelerate the discovery of novel antibiotics from bacterial genomes.

Experimental study of thermohydraulic characteristics and irreversibility analysis of novel axial corrugated tube with spring tape inserts

2020 ◽  
Vol 92 (3) ◽  
pp. 30901
Author(s):  
Suvanjan Bhattacharyya ◽  
Debraj Sarkar ◽  
Ulavathi Shettar Mahabaleshwar ◽  
Manoj K. Soni ◽  
M. Mohanraj
Keyword(s):  
Heat Transfer ◽  
Experimental Study ◽  
Thermal Performance ◽  
Working Fluid ◽  
The Novel ◽  
Heat Exchanger Tube ◽  
Heat Transfer Augmentation ◽  
Corrugated Tube ◽  
The Impact ◽  
Exchanger Tube

The current study experimentally investigates the heat transfer augmentation on the novel axial corrugated heat exchanger tube in which the spring tape is introduced. Air (Pr = 0.707) is used as a working fluid. In order to augment the thermohydraulic performance, a corrugated tube with inserts is offered. The experimental study is further extended by varying the important parameters like spring ratio (y = 1.5, 2.0, 2.5) and Reynolds number (Re = 10 000–52 000). The angular pitch between the two neighboring corrugations and the angle of the corrugation is kept constant through the experiments at β = 1200 and α = 600 respectively, while two different corrugations heights (h) are analyzed. While increasing the corrugation height and decreasing the spring ratio, the impact of the swirling effect improves the thermal performance of the system. The maximum thermal performance is obtained when the corrugation height is h = 0.2 and spring ratio y = 1.5. Eventually, correlations for predicting friction factor (f) and Nusselt number (Nu) are developed.

Wacana Kolonial dalam Novel Max Havelaar: Sebuah Kajian Poskolonial

Metahumaniora ◽  
2017 ◽  
Vol 7 (3) ◽  
pp. 411
Author(s):  
Abu Bakar Ramadhan Muhamad
Keyword(s):  
Point Of View ◽  
The Other ◽  
The Novel ◽  
Colonial Discourse ◽  
The Impact ◽  
The Voice

AbstrakHegemoni kolonialisme dalam budaya poskolonial merupakan alasan penelitian inikemudian mengkaji wacana kolonial dalam novel Max Havellar (MH) khususnya dampakditimbulkannya. Dampak dimaksud adalah posisi keberpihakan pemikiran tersirat darikarya tersebut. Hasil pembahasan menunjukkan, secara temporal maupun permanen MHmenyuarakan ketidakadilan dalam kondisi-kondisi kolonial menyangkut penindasan sangpenjajah terhadap terjajah. Hanya saja, upaya mengatasnamakan atau mewakili suarakaum terjajah terbukti mengimplikasikan ciri ideologis statis kerangka kolonialisme(orientalisme); yakni cara pandang Eropasentris, di mana “Barat” sebagai self adalah superior,dan “Timur” sebagai other adalah inferior. Dalam konteks poskolonialisme, MH dengan sifatkritisnya yang berupaya “menyuarakan” nasib pribumi terjajah, justru menampilkan stigmapenguatan kolonialitas itu sendiri secara hegemonik. Artinya, “menyuarakan” nasib pribumidimaknai sebagai keberpihankan kolonial yang kontradiktif, di mana stigma penguatankolonialitas justru lebih terasa, ujung-ujungnya melanggengkan hegemoni kolonial. Tidakmembela yang terjajah, tetapi memperhalus cara kerja mesin kolonial.AbstractThe hegemony of colonialism in the culture of postcolonial society is the reason this studythen examines the colonial discourse in the novel Max Havellar (MH) in particular the impactit brings. The impact in question is the implied position of thought in the work. The resultsof the discussion show that, temporarily or permanently, MH voiced injustice in the colonialconditions regarding the oppression of the colonist against the colonized. However, the effort toname or represent the voice of the colonized has proven to imply a static ideological characterin the framework of colonialism (orientalism); ie Eropacentric point of view, in which “West” asself is superior, and “East” as the other is the inferior. In the context of postcolonialism, MH withits critical nature that seeks to “voice” the fate of the colonized natives, actually presents thestigma of strengthening coloniality itself hegemonicly. That is, “voicing” the fate of the pribumiis interpreted as a contradictory colonial flare, where the stigma of strengthening colonialityis more pronounced, which ultimately perpetuates the hegemony of colonialism. No longerdefending the colonized, but refining the workings of the colonial machinery.

Total Synthesis of Axially-Chiral Cannabinols: A New Platform for Cannabinoid-Based Drug Discovery

2019 ◽  
Author(s):  
Primali Navaratne ◽  
Jenny Wilkerson ◽  
Kavindri Ranasinghe ◽  
Evgeniya Semenova ◽  
Lance McMahon ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Total Synthesis ◽  
Ground State ◽  
Chemical Space ◽  
Modern Medicine ◽  
The Novel ◽  
Pharmaceutical Development ◽  
Bioactive Component ◽  
Axially Chiral ◽  
New Directions

<div> <div> <div> <p>Phytocannabinoids, molecules isolated from cannabis, are gaining attention as promising leads in modern medicine, including pain management. Considering the urgent need for combating the opioid crisis, new directions for the design of cannabinoid-inspired analgesics are of immediate interest. In this regard, we have hypothesized that axially-chiral-cannabinols (ax-CBNs), unnatural (and unknown) isomers of cannabinol (CBN) may be valuable scaffolds for cannabinoid-inspired drug discovery. There are multiple reasons for thinking this: (a) ax-CBNs would have ground-state three-dimensionality akin to THC, a key bioactive component of cannabis, (b) ax-CBNs at their core structure are biaryl molecules, generally attractive platforms for pharmaceutical development due to their ease of functionalization and stability, and (c) atropisomerism with respect to phytocannabinoids is unexplored “chemical space.” Herein we report a scalable total synthesis of ax-CBNs, examine physical properties experimentally and computationally, and provide preliminary behavioral and analgesic analysis of the novel scaffolds. </p> </div> </div> </div>

Anacyclamide D8P, a prenylated cyanobactin from a Sphaerospermopsis sp. cyanobacterium

2017 ◽  
Author(s):  
Joana Martins ◽  
Niina Leikoski ◽  
Matti Wahlsten ◽  
Joana Azevedo ◽  
Jorge Antunes ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Cyclic Peptides ◽  
Biosynthetic Gene Cluster ◽  
The Novel ◽  
Tyrosine Residue ◽  
Biosynthetic Gene ◽  
Post Translational Modification ◽  
Biological Assays ◽  
Mass Spectrometric Data ◽  
Spectrometric Data

Cyanobactins are a family of linear and cyclic peptides produced through the post-translational modification of short precursor peptides. Anacyclamides are macrocyclic cyanobactins with a highly diverse sequence that are common in the genus <i>Anabaena</i>. A mass spectrometry-based screening of potential cyanobactin producers led to the discovery of a new prenylated member of this family of compounds, anacyclamide D8P (<b>1</b>), from <i>Sphaerospermopsis</i> sp. LEGE 00249. The anacyclamide biosynthetic gene cluster (<i>acy</i>) encoding the novel macrocyclic prenylated cyanobactin, was sequenced. Heterologous expression of the acy gene cluster in <i>Escherichia</i> <i>coli</i> established the connection between genomic and mass spectrometric data. Unambiguous establishment of the type and site of prenylation required the full structural elucidation of <b>1</b> using Nuclear Magnetic Resonance (NMR), which demonstrated that a forward prenylation occurred on the tyrosine residue. Compound <b>1</b> was tested in pharmacologically or ecologically relevant biological assays and revealed moderate antimicrobial activity towards the fouling bacterium <i>Halomonas aquamarina</i> CECT 5000.<br>

Association and treatment of diabetes in patients affected by Covid-19

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 1198-1201
Author(s):  
Syed Yasir Afaque
Keyword(s):  
Diabetes Mellitus ◽  
Prognostic Value ◽  
Heart Diseases ◽  
The Novel ◽  
The World ◽  
Treatment Of Diabetes ◽  
Coronavirus Infection ◽  
Composite Outcomes ◽  
Novel Coronavirus ◽  
The Impact

In December 2019, a unique coronavirus infection, SARS-CoV-2, was first identified in the province of Wuhan in China. Since then, it spread rapidly all over the world and has been responsible for a large number of morbidity and mortality among humans. According to a latest study, Diabetes mellitus, heart diseases, Hypertension etc. are being considered important risk factors for the development of this infection and is also associated with unfavorable outcomes in these patients. There is little evidence concerning the trail back of these patients possibly because of a small number of participants and people who experienced primary composite outcomes (such as admission in the ICU, usage of machine-driven ventilation or even fatality of these patients). Until now, there are no academic findings that have proven independent prognostic value of diabetes on death in the novel Coronavirus patients. However, there are several conjectures linking Diabetes with the impact as well as progression of COVID-19 in these patients. The aim of this review is to acknowledge about the association amongst Diabetes and the novel Coronavirus and the result of the infection in such patients.

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