Decatransin, a novel natural product inhibiting protein translocation at the Sec61/SecY translocon

A new cyclic decadepsipeptide was isolated from Chaetosphaeria tulasneorum with potent bioactivity on mammalian and yeast cells. Chemogenomic profiling in S. cerevisiae indicated that the Sec61 translocon, the machinery for protein translocation and membrane insertion at the endoplasmic reticulum, is the target. The profiles were similar to those of cyclic heptadepsipeptides of a distinct chemotype (HUN-7293/cotransin) that had previously been shown to inhibit cotranslational translocation at the mammalian Sec61 translocon. Unbiased, genome-wide mutagenesis followed by full-genome sequencing in both fungal and mammalian cells identified dominant mutations in Sec61p/Sec61α1 to confer resistance. Most, but not all, of these mutations affected inhibition by both chemotypes, despite an absence of structural similarity. Biochemical analysis confirmed inhibition of protein translocation into the endoplasmic reticulum of both co- and posttranslationally translocated substrates by both chemotypes, demonstrating a mechanism independent of a translating ribosome. Most interestingly, both chemotypes were found to also inhibit SecYEG, the bacterial Sec61 homolog. We suggest "decatransin" as the name for this novel decadepsipeptide translocation inhibitor

Recent developments in antibacterial drug discovery: microbe-derived natural products--from collection to the clinic.

The pharmaceutical industry has historically relied on nature to provide compounds for antibacterial drug discovery. In recent years, several pharmaceutical companies have scaled back their efforts in natural product research. Nevertheless, the screening of natural products for antibacterial activity continues to provide excellent sources of biologically and chemically informative leads for new drugs. New technologies in high-throughput cultivation, genetic approaches to biodiversity and discovery of relatively untapped sources of natural products are expanding the ability to find novel, potent and highly selective antibacterial structures. Advances in purification, dereplication and structure elucidation, combined with the ability to chemically or biologically derivatise hits, aim to make the timeline for natural product-derived drug discovery similar or shorter than that expected for small synthetic molecules. This review addresses the strengths and shortcomings of technologies focused on microbe-derived natural products for antibacterial drug discovery and stresses the need for commitment to these approaches in order to achieve the goal of delivering safe, efficacious and high-quality medicines in the long run

Natural products as probes in pharmaceutical research

From the start of the pharmaceutical research natural products played a key role in drug discovery and development. Over time many discoveries of fundamental new biology were triggered by the unique biological activity of natural products. Unprecedented chemical structures, novel chemotypes, often pave the way to investigate new biology and to explore new pathways and target. This review summarizes the recent results in the area with a focus on research done in the laboratories of Novartis Institutes of BioMedical Research. We aim to put the technological advances in target identification techniques in the context of the current revival of phenotypic screening and the increasingly complex biological questions related to drug discovery

Natural products as catalysts for innovation: a pharmaceutical industry perspective.

There is a constant need for new targets in pharmaceutical research which consequently requires access to novel chemical compounds complementing human genetic or biomarker related approaches. Natural products are evolutionarily designed and chemically distinct from most synthetic library molecules. Besides their role as drugs, they are successfully used to unveil disease relevant targets as molecular probes. Novel natural products can still be discovered from traditional sources through cultivation of microorganisms. Complementary approaches based on genome sequence information and subsequent annotation of biosynthetic pathways are emerging technologies. However, to be of imminent practical use in industrial drug discovery programs, these concepts must be advanced beyond their current state and validated

Nannocystin A: an Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties.

Cultivation of myxobacteria of the Nannocystis genus led to the isolation and structure elucidation of a novel class of cyclic lactone compounds 1-6. Whole genome sequence analysis and annotation enabled identification of the putative biosynthetic cluster and synthesis process. In biological assays the compounds displayed anti-fungal and cytotoxic activity. Combined genetic and proteomic approaches identified the eukaryotic translation elongation factor 1 (EF-1) as the primary target for this compound class that we thus propose to name elongolides. Elongolide A2 (1) displayed differential activity across various cancer cell lines and EEF1A1 expression levels appear to be the main differentiating factor. Biochemical and genetic evidence support an overlapping binding site with the anti-cancer compound didemin B on EF-1. Elongolides thus offer an interesting starting point for further investigations of the potential of therapeutics targeting elongation factor 1

Deliberations on Natural Products and Future Directions in the Pharmaceutical Industry

Natural Products are molecular “special equipment” that impart survival benefits on their producers in nature. Due to their evolved functions to modulate biology these privileged metabolites are substantially represented in the drug market and are continuing to contribute to the discovery of innovative medicines such as the recently approved semi-synthetic derivative of the bacterial alkaloid staurosporin in oncology indications. The innovation of low molecular weight compounds in modern drug discovery is built on rapid progress in chemical, molecular biological, pharmacological and data sciences which together provide a rich understanding of disease-driving molecular interactions and how to modulate them. NPs investigated in these pharmaceutical research areas create new perspectives on their chemical and biological features and thereby new chances to advance medical research. New methods in analytical chemistry linked with searchable NP-databases solved the issue of reisolation and enabled targeted and efficient access to novel molecules from nature. Cheminformatics delivers high resolution descriptions of NPs and explores the substructures that systematically map NP-chemical space by sp3-enriched fragments. Whole genome sequencing has revealed the existence of collocated gene clusters that form larger functional entities together with proximate resistance factors thus avoiding self-inhibition of the encoded metabolites. The analysis of bacterial and fungal genes provides tantalizing glimpses of new compound-target pairs of therapeutic value. Furthermore, a dedicated investigation of structurally unique, selectively active NPs in chemical biology demonstrates their extraordinary power as shuttles between new biological target spaces of pharmaceutical relevance

Discovery of the actinoplanic acid pathway in Streptomyces rapamycinicus reveals a genetically conserved synergism with rapamycin

Actinobacteria possess a great wealth of pathways for production of bioactive compounds. Following advances in genome mining, dozens of natural product (NP) gene clusters are routinely found in each actinobacterial genome; however, the modus operandi of this large arsenal is poorly understood. During investigations of the secondary metabolome of Streptomyces rapamycinicus, the producer of rapamycin, we observed accumulation of two compounds never before reported from this organism. Structural elucidation revealed actinoplanic acid A and its demethyl analogue. Actinoplanic acids (APLs) are potent inhibitors of Ras farnesyltransferase and therefore represent bioactive compounds of medicinal interest. Supported with the unique structure of these polyketides and using genome mining, we identified a gene cluster responsible for their biosynthesis in S. rapamycinicus Based on experimental evidence and genetic organization of the cluster, we propose a stepwise biosynthesis of APL, the first bacterial example of a pathway incorporating the rare tricarballylic moiety into an NP. Although phylogenetically distant, the pathway shares some of the biosynthetic principles with the mycotoxins fumonisins. Namely, the core polyketide is acylated with the tricarballylate by an atypical nonribosomal peptide synthetase-catalyzed ester formation. Finally, motivated by the conserved colocalization of the rapamycin and APL pathway clusters in S. rapamycinicus and all other rapamycin-producing actinobacteria, we confirmed a strong synergism of these compounds in antifungal assays. Mining for such evolutionarily conserved coharboring of pathways would likely reveal further examples of NP sets, attacking multiple targets on the same foe. These could then serve as a guide for development of new combination therapies

Evaluation of antibacterial activity of the crude and defatted methanol extracts of Eucalyptus Camaldulensis using spectrophotometric method

This study was designed to explore new antibacterial agent(s) from the crude and defatted methanol extracts of Eucalyptus camaldulensis. The extracts were extracted by cold maceration, prepared, reconstituted and examined for their antibacterial activity using standard procedures. The extracts were challenged with pure clinical isolates of Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, Acinectobacter baumanii and Burkolderia cepacia viz-a-viz standard antibiotics of chloramphenicol, gentamicin and amoxicillin at 25 μg/ml, 50 μg/ml and 100 μg/ml concentrations using spectrophotometric method. Using the zone of inhibition as inhibitory parameter, both the crude and defatted methanol extracts of E. camaldulensis showed promising antimicrobial activity comparable to the standard antibiotics for all tested microorganisms. This research holds promise for the exploration of various potentially active secondary metabolites which would help in developing pharmaceuticals especially antibacterial drugs. The isolation and characterization of the exact metabolites responsible for these activities are therefore highly recommended. Keywords: Antimicrobial, Eucalyptus camaldulesnsis, Spectrophotometric metho

Digital elevation models measured at three different sites off the island of Sylt (German Bight, SE North Sea), link to DEM in MatLab format

This study presents a new in situ method to explore the impact of macrofauna on seafloor microtopography and corresponding microroughness based on underwater laser line scanning. The local microtopography was determined with mm-level accuracy at three stations colonised by the tubeworm Lanice conchilega offshore of the island of Sylt in the German Bight (south-eastern North Sea), covering approximately 0.5 m**2 each. Ground truthing was done using underwater video data. Two stations were populated by tubeworm colonies of different population densities, and one station had a hydrodynamically rippled seafloor. Tubeworms caused an increased skewness of the microtopography height distribution and an increased root mean square roughness at short spatial wavelengths compared with hydrodynamic bedforms. Spectral analysis of the 2D Fourier transformed microtopography showed that the roughness magnitude increased at spatial wavelengths between 0.020 and 0.003 m independently of the tubeworm density. This effect was not detected by commonly used 1D roughness profiles but required consideration of the complete spectrum. Overall, the results reveal that new indicator variables for benthic organisms may be developed based on microtopographic data. An example demonstrates the use of local slope and skewness to detect tubeworms in the measured digital elevation model