Identification and Heterologous Expression of the Albucidin Gene Cluster from the Marine Strain Streptomyces Albus Subsp. Chlorinus NRRL B-24108

Herbicides with new modes of action and safer toxicological and environmental profiles are needed to manage the evolution of weeds that are resistant to commercial herbicides. The unparalleled structural diversity of natural products makes these compounds a promising source for new herbicides. In 2009, a novel nucleoside phytotoxin, albucidin, with broad activity against grass and broadleaf weeds was isolated from a strain of Streptomyces albus subsp. chlorinus NRRL B-24108. Here, we report the identification and heterologous expression of the previously uncharacterized albucidin gene cluster. Through a series of gene inactivation experiments, a minimal set of albucidin biosynthetic genes was determined. Based on gene annotation and sequence homology, a model for albucidin biosynthesis was suggested. The presented results enable the construction of producer strains for a sustainable supply of albucidin for biological activity studies

Novel Fredericamycin Variant Overproduced by a Streptomycin-Resistant Streptomyces albus subsp. chlorinus Strain

Streptomycetes are an important source of natural products potentially applicable in the pharmaceutical industry. Many of these drugs are secondary metabolites whose biosynthetic genes are very often poorly expressed under laboratory cultivation conditions. In many cases, antibiotic-resistant mutants exhibit increased production of natural drugs, which facilitates the identification and isolation of new substances. In this study, we report the induction of a type II polyketide synthase gene cluster in the marine strain Streptomyces albus subsp. chlorinus through the selection of streptomycin-resistant mutants, resulting in overproduction of the novel compound fredericamycin C2 (1). Fredericamycin C2 (1) is structurally related to the potent antitumor drug lead fredericamycin A

To meat or not to meat? New perspectives on Neanderthal ecology.

Neanderthals have been commonly depicted as top predators who met their nutritional needs by focusing entirely on meat. This information mostly derives from faunal assemblage analyses and stable isotope studies: methods that tend to underestimate plant consumption and overestimate the intake of animal proteins. Several studies in fact demonstrate that there is a physiological limit to the amount of animal proteins that can be consumed: exceeding these values causes protein toxicity that can be particularly dangerous to pregnant women and newborns. Consequently, to avoid food poisoning from meat-based diets, Neanderthals must have incorporated alternative food sources in their daily diets, including plant materials as well

Identification and Heterologous Expression of the Albucidin Gene Cluster from the Marine Strain Subsp. NRRL B-24108.

Herbicides with new modes of action and safer toxicological and environmental profiles are needed to manage the evolution of weeds that are resistant to commercial herbicides. The unparalleled structural diversity of natural products makes these compounds a promising source for new herbicides. In 2009, a novel nucleoside phytotoxin, albucidin, with broad activity against grass and broadleaf weeds was isolated from a strain of Streptomyces albus subsp. chlorinus NRRL B-24108. Here, we report the identification and heterologous expression of the previously uncharacterized albucidin gene cluster. Through a series of gene inactivation experiments, a minimal set of albucidin biosynthetic genes was determined. Based on gene annotation and sequence homology, a model for albucidin biosynthesis was suggested. The presented results enable the construction of producer strains for a sustainable supply of albucidin for biological activity studies

Identification and Heterologous Expression of the Albucidin Gene Cluster from the Marine Strain Streptomyces Albus Subsp. Chlorinus NRRL B-24108

Herbicides with new modes of action and safer toxicological and environmental profiles are needed to manage the evolution of weeds that are resistant to commercial herbicides. The unparalleled structural diversity of natural products makes these compounds a promising source for new herbicides. In 2009, a novel nucleoside phytotoxin, albucidin, with broad activity against grass and broadleaf weeds was isolated from a strain of Streptomyces albus subsp. chlorinus NRRL B-24108. Here, we report the identification and heterologous expression of the previously uncharacterized albucidin gene cluster. Through a series of gene inactivation experiments, a minimal set of albucidin biosynthetic genes was determined. Based on gene annotation and sequence homology, a model for albucidin biosynthesis was suggested. The presented results enable the construction of producer strains for a sustainable supply of albucidin for biological activity studies

Novel Fredericamycin Variant Overproduced by a Streptomycin-resistant subsp. Strain.

Streptomycetes are an important source of natural products potentially applicable in the pharmaceutical industry. Many of these drugs are secondary metabolites whose biosynthetic genes are very often poorly expressed under laboratory cultivation conditions. In many cases, antibiotic-resistant mutants exhibit increased production of natural drugs, which facilitates the identification and isolation of new substances. In this study, we report the induction of a type II polyketide synthase gene cluster in the marine strain Streptomyces albus subsp. chlorinus through the selection of streptomycin-resistant mutants, resulting in overproduction of the novel compound fredericamycin C2 (1). Fredericamycin C2 (1) is structurally related to the potent antitumor drug lead fredericamycin A

Novel Fredericamycin Variant Overproduced by a Streptomycin-Resistant Streptomyces albus subsp. chlorinus Strain

Streptomycetes are an important source of natural products potentially applicable in the pharmaceutical industry. Many of these drugs are secondary metabolites whose biosynthetic genes are very often poorly expressed under laboratory cultivation conditions. In many cases, antibiotic-resistant mutants exhibit increased production of natural drugs, which facilitates the identification and isolation of new substances. In this study, we report the induction of a type II polyketide synthase gene cluster in the marine strain Streptomyces albus subsp. chlorinus through the selection of streptomycin-resistant mutants, resulting in overproduction of the novel compound fredericamycin C2 (1). Fredericamycin C2 (1) is structurally related to the potent antitumor drug lead fredericamycin A

An influence of the copy number of biosynthetic gene clusters on the production level of antibiotics in a heterologous host

Manderscheid N, Bilyk B, Busche T, et al. An influence of the copy number of biosynthetic gene clusters on the production level of antibiotics in a heterologous host. JOURNAL OF BIOTECHNOLOGY. 2016;232:110-117.Streptomyces albus J1074 is a well-known host for heterologous expression of secondary metabolites. To further increase its potential and to study the influence of cluster multiplication, additional phi C31 attachment site was integrated into its genome using a system for transposon mutagenesis. Four secondary metabolite clusters were expressed in strains with different numbers of attachment sites, ranging from one to three copies of the site. Secondary metabolite production was examined and a new compound could be detected, purified and its structure was elucidated. (C) 2016 Elsevier B.V. All rights reserved

Rewiring of the Austinoid Biosynthetic Pathway in Filamentous Fungi

Filamentous fungi produce numerous high-value natural products (NPs). The biosynthetic genes for NPs are normally clustered in the genome. A valuable NP class is represented by the insecticidal austinoids. We previously determined their biosynthesis in the fungus <i>Aspergillus calidoustus</i>. After further computational analysis looking into the austinoid gene clusters in two additional distantly related fungi, <i>Aspergillus nidulans</i> and <i>Penicillium brasilianum</i>, a rearrangement of the genes was observed that corresponded to the diverse austinoid derivatives produced by each strain. By advanced targeted combinatorial engineering using polycistronic expression of selected genes, we rewired the austinoid pathway in the fungus <i>A. nidulans</i>, which then produced certain compounds of interest under industrially favored conditions. This was possible by exploiting the presence of genes previously thought to be irrelevant. Our work shows that comparative analysis of genomes can be used to not only discover new gene clusters but unearth the hidden potential of known metabolic pathways

Lower Placebo Responses After Long-Term Exposure to Fibromyalgia Pain

Knowledge about placebo mechanisms in patients with chronic pain is scarce. Fibromyalgia syndrome (FM) is associated with dysfunctions of central pain inhibition, and because placebo analgesia entails activation of endogenous pain inhibition, we hypothesized that long-term exposure to FM pain would negatively affect placebo responses. In our study we examined the placebo group (n = 37, mean age 45 years) from a 12-week, randomized, double-blind, placebo-controlled trial investigating the effects of milnacipran or placebo. Twenty-two patients were classified as placebo non responders and 15 as responders, according to the Patient Global Impression of Change scale. Primary outcome was the change in pressure pain sensitivity from baseline to post-treatment. Secondary outcomes included ratings of clinical pain (visual analog scale), FM effect (Fibromyalgia Impact Questionnaire), and pain drawing. Among placebo responders, longer FM duration was associated with smaller reductions in pressure pain sensitivity (r=.689, P=.004), but not among nonresponders (r=.348, P=.112). In our study we showed that FM duration influences endogenous pain regulation, because pain levels and placebo-induced analgesia were negatively affected. Our results point to the importance of early FM interventions, because endogenous pain regulation may still be harnessed at that early time. Also, placebo-controlled trials should take FM duration into consideration when interpreting results. Perspective: This study presents a novel perspective on placebo analgesia, because placebo responses among patients with chronic pain were analyzed. Long-term exposure to fibromyalgia pain was associated with lower placebo analgesia, and the results show the importance of taking pain duration into account when interpreting the results from placebo-controlled trials. (C) 2017 The Authors. Published by Elsevier Inc. on behalf of the American Pain Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)