SciCombinator

Discover the most talked about and latest scientific content & concepts.

Journal: The Journal of antibiotics

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Despite the growing threat of antimicrobial resistance, pharmaceutical and biotechnology firms are reluctant to develop novel antibiotics because of a host of market failures. This problem is complicated by public health goals that demand antibiotic conservation and equitable patient access. Thus, an innovative incentive strategy is needed to encourage sustainable investment in antibiotics. This systematic review consolidates, classifies and critically assesses a total of 47 proposed incentives. Given the large number of possible strategies, a decision framework is presented to assist with the selection of incentives. This framework focuses on addressing market failures that result in limited investment, public health priorities regarding antibiotic stewardship and patient access, and implementation constraints and operational realities. The flexible nature of this framework allows policy makers to tailor an antibiotic incentive package that suits a country’s health system structure and needs.The Journal of Antibiotics advance online publication, 14 October 2015; doi:10.1038/ja.2015.98.

Concepts: Medicine, Public health, Bacteria, Antibiotic resistance, Policy, Microorganism, Penicillin, Microeconomics

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Five new phenethylamine (PEA) derivatives (1-5) were isolated from the strain of Arenibacter nanhaiticus sp. nov. NH36A(T) derived from the marine sediment of the South China Sea by bioassay-guided fractionation. Their structures were elucidated by spectroscopic methods including UV, IR, HR-MS and NMR. Interestingly, compounds 1-4 existed as enantiomers, which were resolved by chiral liquid chromatography. The resolved configuration of each enantiomer was assigned by the Marfey’s method. Of these compounds, 5 showed weak antimicrobial activity against Staphylococcus aureus and Bacillus subtilis with MIC values of 0.50 and 0.25 mg ml(-1), respectively.The Journal of Antibiotics advance online publication, 17 July 2013; doi:10.1038/ja.2013.65.

Concepts: Bacteria, Microbiology, Staphylococcus aureus, Enantiomer, Chirality, Bacillus, Bacillus subtilis, South China Sea

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Clavulanic acid (CA) is a potent β-lactamase inhibitor produced by Streptomyces clavuligerus and has been successfully used in combination with β-lactam antibiotics (for example, Augmentin) to treat infections caused by β-lactamase-producing pathogens. Since the discovery of CA in the late 1970s, significant information has accumulated on its biosynthesis, and regarding molecular mechanisms involved in the regulation of its production. Notably, the genes directing CA biosynthesis are clustered along with the genes responsible for the biosynthesis of the β-lactam antibiotic, cephamycin C, and co-regulated, which makes this organism unique in that the production of an antibiotic and production of a small molecule to protect the antibiotic from its enzymatic degradation are controlled by shared mechanisms. Traditionally, the industrial strain improvement programs have relied significantly on random mutagenesis and selection approach. However, the recent availability of the genome sequence of S. clavuligerus along with the capability to build metabolic models, and ability to engineer the organism by directed approaches, has created exciting opportunities to improve strain productivity more efficiently. This review will include focus mainly on the gene organization of the CA biosynthetic genes, regulatory mechanisms that affect its production, and will include perspectives on improving strain productivity.The Journal of Antibiotics advance online publication, 24 April 2013; doi:10.1038/ja.2013.26.

Concepts: DNA, Protein, Gene, Bacteria, Organism, Virus, Genome, Clavulanic acid

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Streptomyces chrysomallus and Streptomyces parvulus produce novel C-demethylactinomycins besides their normal actinomycins when fed with 3-hydroxyanthranilic acid (3-HA). The 3-HA is incorporated into pentapeptide lactone precursors in competition with the regular precursor 4-methyl-3-hydroxyanthranilic acid (4-MHA). The resultant 3-HA pentapeptide lactones can condense with each other, as well as with the continuously formed 4-MHA pentapeptide lactones giving C-demethylactinomycins lacking one or both methyl groups in their phenoxazinone chromophores. In case of C-demethylactinomyins lacking one methyl group, the condensation was shown to be regiospecific directing the 3-HA portion almost exclusively to the α-side of the phenoxazinone chromophore. As 3-HA is a weaker substrate for the 4-MHA-incorporating enzyme actinomycin synthetase I than 4-MHA, C-demethylactinomycins never exceeded 7-8% of total actinomycin formed. Surprisingly, C-demethylactinomycins (up to 0.8%) were also found in the actinomycin mixtures of unsupplemented streptomycete cultures after longer cultivation times, indicating the natural presence of 3-HA. Feeding with 3-hydroxykynurenine (3-HK) induced also formation of C-demethylactinomycins indicating that 3-HK is source of 3-HA. Analysis of tryptophan metabolites in the intracellular pools of the streptomycetes using 5-(3)H-tryptophan as radiotracer revealed formation of 4-MHA, but not of 3-HA. This indicates that intracellular 3-HK is almost exclusively converted to 3-hydroxy-4-methylkynurenine (4-MHK), which has been identified previously as direct precursor of 4-MHA. However, small amount of 3-HK leaking out from the 4-MHA pathway can be prematurely converted to 3-HA all along the cultivation of the streptomycetes resulting in the formation of natural C-demethylactinomycins.The Journal of Antibiotics advance online publication, 20 February 2013; doi:10.1038/ja.2012.120.

Concepts: Amino acid, Enzyme, Protein precursor, Methyl group, Condensation, Streptomyces, Streptomycetaceae

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The stereoselective total synthesis of garsubellin A is described. The total synthesis was achieved through the stereoselective construction of a bicyclo[3.3.1]nonane derivative via a three-step sequence: intramolecular cyclopropanation, formation of a germinal dimethyl group, and regioselective ring opening of cyclopropane. To complete the total synthesis of garsubellin A, chemo- and stereoselective hydrogenation to generate the C8 stereogenic center is followed by the formation of the fused tetrahydrofuran ring by a regioselective epoxide-opening reaction with C3 ketone, and finally cross metathesis to construct two prenyl groups.The Journal of Antibiotics advance online publication, 6 February 2013; doi:10.1038/ja.2012.125.

Concepts: Stereochemistry, Total synthesis, Mathematical analysis, Vector space, Alkane, Stereocenter, Construction, Cyclopropane

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Infectious diseases caused by chlamydia or schistosomes are a major health problem worldwide, and particularly so in developing countries. The lack of appropriate vaccines renders the search for potent natural products against these disease-causing agents an urgent endeavor. Sponge-associated actinomycetes represent a rich reservoir for natural products. Among them, members of the genus Streptomyces are capable of synthesizing an impressive array of diverse natural products with a wide variety of biological activities. The naphthacene glycoside SF2446A2 was isolated from the calcium alginate beads culture of Streptomyces sp. strain RV15 that had originally been obtained from the Mediterranean sponge Dysidea tupha. Its structure was identified by spectroscopic analysis and MS and comparison with the literature data. SF2446A2 showed inhibitory activity against Chlamydia trachomatis and was able to inhibit the primary infection in a dose-dependent manner, as well as progeny formation. Moreover, it caused disruptive effects on the surface area of Schistosoma mansoni and affected the gonads by impairing oogenesis and spermatogenesis. Our current study demonstrates that sponge-associated actinomycetes are capable of providing compounds with new pharmacological activities and with relevance to drug discovery.The Journal of Antibiotics advance online publication, 20 May 2015; doi:10.1038/ja.2015.54.

Concepts: Infectious disease, Infection, Schistosoma mansoni, Schistosoma, Chlamydiae, Chlamydia, Chlamydia trachomatis, Streptomyces

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Infections with Cryptococcus are invasive mycoses associated with significant morbidity and mortality, mainly in immunosuppressed patients. Several drugs have been introduced to combat these opportunistic infections. However, resistance of this organism to antifungal drugs has increased, causing difficulties in the treatment. The goal of this work was to evaluate the antifungal activity of ethanol extracts from endophytic fungi isolated from plants collected from different Brazilian ecosystems and to perform the fractionation of the most promising extract. Four-hundred fungal extracts were investigated by microdilution broth assays against Cryptococcus neoformans and Cryptococcus gattii at a concentration of 500 μg ml(-1). Among them, the extract of Mycosphaerella sp. UFMGCB 2032, an endophytic fungus isolated from the plant Eugenia bimarginata DC. (Myrtaceae) exhibited outstanding antifungal activity against C. neoformans and C. gattii, with MIC values of 31.2 μg ml(-1) and 7.8 μg ml(-1), respectively. The fractionation of this extract using liquid-liquid partitioning and semi-preparative HPLC afforded two eicosanoic acids with antifungal activity, compound 1, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-(hydroxymethyl)-14-oxoeicos-6,12-dienoic acid with MIC values ranging from 1.3-2.50 μg ml(-1), and compound 2, known as myriocin, with MIC values of 0.5 μg ml(-1) against C. neoformans and C. gattii. These compounds are reported for the first time in the Mycosphaerella genus.The Journal of Antibiotics advance online publication, 25 February 2015; doi:10.1038/ja.2015.11.

Concepts: AIDS, Plant, Fungus, Yeast, Cryptococcus neoformans, Basidiomycota, Cryptococcus

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Actinomycetes are a major source of bioactive secondary metabolites and are a focal point in the search for novel antimicrobial compounds that are needed to combat multidrug-resistant pathogens. Here, we report the discovery of several novel phenazine-type antibiotics produced by Kitasatospora sp. MBT66. These include the novel glycosylated endophenazines A-E (1-5), together with N-prenylated endophenazine F1 (6). Compounds 1 and 3 contain a 2'-O-methylation of the sugar moiety, which is rare in nature and reported for the first time in connection with phenazines. The structures of the new compounds were determined on the basis of their spectral data, including 1D and 2D NMR, HR-MS and the gene cluster responsible for the biosynthesis of phenazines was identified. All phenazine derivatives showed antimicrobial activity against the Gram-positive Bacillus subtilis, while compounds 1-3 and 5 also inhibited growth of the Gram-negative Escherichia coli.The Journal of Antibiotics advance online publication, 18 February 2015; doi:10.1038/ja.2015.14.

Concepts: DNA, Bacteria, Metabolism, Microbiology, Bacillus, Bacillus subtilis

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Two new benzoxazines were isolated from Streptomyces griseus (HKI 0545) and assigned as chandrananimycin E (1) and dandamycin (2). Although a number of phenoxazinone-type compounds have been reported from nature, phenoxazines are rarer, and carbon substitution at N-10 such as in 1 is unprecedented. The cyclopentene-containing ring structure of dandamycin (2) is also unique. Chandrananimycin E (1) was found to possess moderate antiproliferative activity against HUVEC cells (GI50 35.3 μM) and weak cytotoxic activity towards HeLa cells (CC50 56.9 μM). Dandamycin showed neither antiproliferative activity nor cytotoxicity towards these cell lines. Structure activity comparisons with phenoxazinones isolated from S. griseus HKI 0545 suggested that the alteration of the core ring systems in 1 and 2 diminishes their activity. Natural products 1 and 2 are interesting additions to the rich secondary metabolome of S. griseus and constitute an important addition to the body of knowledge on phenoxazinone-derived metabolites.The Journal of Antibiotics advance online publication, 18 February 2015; doi:10.1038/ja.2015.10.

Concepts: Cell, Bacteria, Cell culture, Addition, HeLa, Cytotoxicity, Streptomyces, Streptomyces griseus

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In our effort to find the key intermediates of lankacidin biosynthesis in Streptomyces rochei, three UV-active compounds were isolated from mutant FS18, a gene disruptant of lkcA encoding a non-ribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) hybrid enzyme. Their structures were elucidated on the basis of spectroscopic data of NMR and MS. Two compounds of a higher mobile spot on silica gel TLC (Rf=0.45 in CHCl3-MeOH=20:1) were determined to be an epimeric mixture of citreodiol and epi-citreodiol at the C-6 position in the ratio of 2:1. In contrast, the compound of a lower mobile spot (Rf=~0 in CHCl3-MeOH=20:1) was identical to a 28-membered polyene macrolide pentamycin. The yields of citreodiols and pentamycin in FS18 were 5- and 250-fold higher compared with the parent strain. Introduction of a second mutation of srrX, coding a biosynthetic gene of the signaling molecules SRBs, into mutant FS18 did not affect the production of three metabolites. Thus, their production was not regulated by the SRB signaling molecules in contrast to lankacidin or lankamycin.The Journal of Antibiotics advance online publication, 3 December 2014; doi:10.1038/ja.2014.160.

Concepts: DNA, Protein, Gene, Bacteria, Amino acid, Metabolism, Ratio, Chemical compound