Marine actinomycetes as an emerging resource for the drug development pipelines

Zotchev, Sergey B.

doi:10.1016/j.jbiotec.2011.06.002

Cited by 149 publications

(87 citation statements)

References 69 publications

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“…Marine actinomyces are one of the most prolific groups of bioactive secondary metabolite producers (Fiedler et al, 2005). These microbes produce a variety of chemical structures including terpenoids, peptides, macrolides, polycyclic compounds, and quinones (Zotchev, 2012). The structural diversity and wide range of bioactivity have established marine natural products as a promising frontier in future drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Identification of Protein Kinase C Activation as a Novel Mechanism for RGS2 Protein Upregulation through Phenotypic Screening of Natural Product Extracts

et al. 2014

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Biochemical high-throughput screening is widely used in drug discovery, using a variety of small molecule libraries. However, broader screening strategies may be more beneficial to identify novel biologic mechanisms. In the current study we used a b-galactosidase complementation method to screen a selection of microbial-derived pre-fractionated natural product extracts for those that increase regulator of G protein signaling 2 (RGS2) protein levels. RGS2 is a member of a large family of proteins that all regulate signaling through G protein-coupled receptors (GPCRs) by accelerating GTPase activity on active Ga as well as through other mechanisms. RGS22/2 mice are hypertensive, show increased anxiety, and are prone to heart failure. RGS2 has a very short protein halflife due to rapid proteasomal degradation, and we propose that enhancement of RGS2 protein levels could be a beneficial therapeutic strategy. Bioassay-guided fractionation of one of the hit strains yielded a pure compound, Indolactam V, a known protein kinase C (PKC) activator, which selectively increased RGS2 protein levels in a time-and concentrationdependent manner. Similar results were obtained with phorbol 12-myristate 13-acetate as well as activation of the Gqcoupled muscarinic M 3 receptor. The effect on RGS2 protein levels was blocked by the nonselective PKC inhibitor Gö6983 (3-[1-[3-(dimethylamino)propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione), the PKCb-selective inhibitor Ruboxastaurin, as well as small interfering RNA-mediated knockdown of PKCb. Indolactam V-mediated increases in RGS2 protein levels also had functional effects on GPCR signaling. This study provides important proof-of-concept for our screening strategy and could define a negative feedback mechanism in Gq/Phospholipase C signaling through RGS2 protein upregulation.

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Section: Introductionmentioning

confidence: 99%

Identification of Protein Kinase C Activation as a Novel Mechanism for RGS2 Protein Upregulation through Phenotypic Screening of Natural Product Extracts

et al. 2014

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“…Su contraparte terrestre ha sido utilizada por la industria farmacéutica y el estudio de fuentes marinas se ha intensificado identificándose numerosos compuestos con actividad antibacteriana, citotóxica y antiinflamatoria [89]. Se destacan como antibacterianos la abisomicina C, throughput screening (HTS) pone reactivar el estudio de fuentes naturales de antibióticos, considerando el aporte de metabolitos secundarios (sustancias producidas por los organismos que no comprometen su supervivencia) en la actividad antibacteriana [46].…”

Section: Reactivación De La Investigación De Productos Naturalesunclassified

“…Su contraparte terrestre ha sido utilizada por ria farmacéutica y el estudio de fuentes marinas se ha intensificado identificándose numerosos compuestos con actividad antibacteriana, citotóxica y antiinflamatoria [89]. Se destacan como antibacterianos la abisomicina C, carboxamicina, esrramicina, enter (bacteriostático), linamicinas, salinosporamida A, TP-1161, entre otros [46,89].…”

Section: Reactivación De La Investigación De Productos Naturalesunclassified

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Actualidades en terapéutica: nuevos antibacterianos

Cano

Madrigal

2014

Rev.Med.UCR

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Resumen: La resistencia bacteriana a antibióticos es un problema con enormes repercusiones a nivel de la salud pública mundial, incluyendo Costa Rica. Esta situación ha llevado a organizaciones internacionales a tomar medidas encaminadas a mitigar el problema. Dentro de las medidas sugeridas se incluyen: la identificación de los microorganismos bacterianos multirresistentes, la vigilancia epidemiológica, la implementación de estrategias que minimicen la resistencia y el desarrollo de n de esta última sugerencia, este trabajo analiza los nuevos antibacterianos aprobados por agencias reguladoras en el periodo 2007-2014, así como los fármacos en fases II y III de desarrollo en Estados Unidos y Europa. Los datos obtenidos evidencian que la mayor parte de los fármacos nuevos son modificaciones de moléculas de familias conocidas, llamando la atención sobre la necesidad de innovar las estrategias farmacológicas. Otras alternativas analizadas, aún en investigación, son mecanismos de acción no tradicionales, que incluye el aislamiento de lantibióticos, el estudio de fuentes marinas, la síntesis de híbridos, la investigación de péptidos antimicrobianos, el uso de bacteriófagos y el desarrollo de fármacos que modifiquen la virulencia. Se concluye que a pesar de la extensa investigación en el tema, en muchos casos, esta no se ha traducido en opciones disponibles para uso médico. La resistencia bacteriana a antibióticos es un problema con enormes repercusiones a nivel de la salud pública mundial, incluyendo Costa Rica. Esta situación ha llevado a organizaciones internacionales a das a mitigar el problema. Dentro de las medidas sugeridas se incluyen: la identificación de los microorganismos bacterianos multirresistentes, la vigilancia epidemiológica, la implementación de estrategias que minimicen la resistencia y el desarrollo de n de esta última sugerencia, este trabajo analiza los nuevos antibacterianos aprobados por agencias 2014, así como los fármacos en fases II y III de desarrollo en Estados Unidos y btenidos evidencian que la mayor parte de los fármacos nuevos son modificaciones de moléculas de familias conocidas, llamando la atención sobre la necesidad de innovar las estrategias farmacológicas. Otras alternativas analizadas, aún en investigación, son el desarrollo de fármacos con mecanismos de acción no tradicionales, que incluye el aislamiento de lantibióticos, el estudio de fuentes marinas, la síntesis de híbridos, la investigación de péptidos antimicrobianos, el uso de bacteriófagos y el o de fármacos que modifiquen la virulencia. Se concluye que a pesar de la extensa investigación en el tema, en muchos casos, esta no se ha traducido en opciones disponibles para uso médico. La resistencia bacteriana a antibióticos es un problema con enormes repercusiones a nivel de la salud pública mundial, incluyendo Costa Rica. Esta situación ha llevado a organizaciones internacionales a das a mitigar el problema. Dentro de las medidas sugeridas se incluyen: la identificación de los microorganismos bacterianos multirresistentes, ...

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“…including S. griseus, S. hygroscopicus, S. coelicolor, S. avermitilis, S. rochei, S. plicatus, S. fungicidicus, S. flaveus, and S. globisporus; belonging to different classes of antibiotics such as aminoglycosides, ansamycins, anthracyclines, glycopeptides, β-lactams, macrolides, nucleosides, peptides, polyenes, polyethers, and tetracyclines [6][7][8]. These organisms are of high biotechnological and commercial values; and continue to be routinely screened for new bioactive compounds [9][10][11]. Streptomyces spp.…”

Section: Introductionmentioning

confidence: 99%

Phylogenetic Characterization of Culturable Antibiotic Producing Streptomyces from Rhizospheric Soils

Babalola¹

2014

Mol Biol

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Streptomyces spp. were isolated from rhizospheric soils collected from Ngaka Modiri Molema District, North West Province, South Africa. Ten of these bacterial isolates were found to exhibit broad spectrum antimicrobial activity against test organisms with varying degree of activity. The cultural characteristics of the bacterial isolates were consistent with that of the members of the genus Streptomyces. Molecular identification of the potent bacterial isolates was carried out by amplifying the 16S rDNA gene; this gave the expected size of 1.5 kb and was sequenced. Further computational analysis including BLAST search and phylogenetic analysis were performed to correlate the bacterial isolates with other species of the genera in the database library. The computational analysis of the amplified 16S rDNA gene confirmed that the bacterial isolates are members of the genus Streptomyces with 89-100% sequence similarity. The phylogenetic analysis showed that the 10 bacterial isolates were divided into 3 major clusters with varying bootstrap values. The strain NWU195 formed a distinct phyletic line in the Streptomyces 16S rDNA gene tree suggesting a new strain. The 16S rDNA sequences of the bacterial isolates was submitted to the GenBank under the accession numbers JX284398-JX284407. The 16S rDNA gene sequence analysis is a significant tool for phylogenetic analysis of Streptomyces spp.

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Marine actinomycetes as an emerging resource for the drug development pipelines

Cited by 149 publications

References 69 publications

Identification of Protein Kinase C Activation as a Novel Mechanism for RGS2 Protein Upregulation through Phenotypic Screening of Natural Product Extracts

Identification of Protein Kinase C Activation as a Novel Mechanism for RGS2 Protein Upregulation through Phenotypic Screening of Natural Product Extracts

Actualidades en terapéutica: nuevos antibacterianos

Phylogenetic Characterization of Culturable Antibiotic Producing Streptomyces from Rhizospheric Soils

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