Publications by authors named "Chambers C Hughes"

32 Publications

Chemical labeling strategies for small molecule natural product detection and isolation.

Nat Prod Rep 2021 Feb 25. Epub 2021 Feb 25.

Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, Germany 72076.

Covering: Up to 2020.It is widely accepted that small molecule natural products (NPs) evolved to carry out a particular ecological function and that these finely-tuned molecules can sometimes be appropriated for the treatment of disease in humans. Unfortunately, for the natural products chemist, NPs did not evolve to possess favorable physicochemical properties needed for HPLC-MS analysis. The process known as derivatization, whereby an NP in a complex mixture is decorated with a nonnatural moiety using a derivatizing agent (DA), arose from this sad state of affairs. Here, NPs are freed from the limitations of natural functionality and endowed, usually with some degree of chemoselectivity, with additional structural features that make HPLC-MS analysis more informative. DAs that selectively label amines, carboxylic acids, alcohols, phenols, thiols, ketones, and aldehydes, terminal alkynes, electrophiles, conjugated alkenes, and isocyanides have been developed and will be discussed here in detail. Although usually employed for targeted metabolomics, chemical labeling strategies have been effectively applied to uncharacterized NP extracts and may play an increasing role in the detection and isolation of certain classes of NPs in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0np00034eDOI Listing
February 2021

Multiple genes recruited from hormone pathways partition maize diterpenoid defences.

Nat Plants 2019 10 16;5(10):1043-1056. Epub 2019 Sep 16.

Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA, USA.

Duplication and divergence of primary pathway genes underlie the evolution of plant specialized metabolism; however, mechanisms partitioning parallel hormone and defence pathways are often speculative. For example, the primary pathway intermediate ent-kaurene is essential for gibberellin biosynthesis and is also a proposed precursor for maize antibiotics. By integrating transcriptional coregulation patterns, genome-wide association studies, combinatorial enzyme assays, proteomics and targeted mutant analyses, we show that maize kauralexin biosynthesis proceeds via the positional isomer ent-isokaurene formed by a diterpene synthase pair recruited from gibberellin metabolism. The oxygenation and subsequent desaturation of ent-isokaurene by three promiscuous cytochrome P450s and a new steroid 5α reductase indirectly yields predominant ent-kaurene-associated antibiotics required for Fusarium stalk rot resistance. The divergence and differential expression of pathway branches derived from multiple duplicated hormone-metabolic genes minimizes dysregulation of primary metabolism via the circuitous biosynthesis of ent-kaurene-related antibiotics without the production of growth hormone precursors during defence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41477-019-0509-6DOI Listing
October 2019

Progress toward the Total Synthesis of Lymphostins: Preparation of a Functionalized Tetrahydropyrrolo[4,3,2-]quinoline and Unusual Oxidative Dimerization.

J Org Chem 2019 07 27;84(14):9339-9343. Epub 2019 Jun 27.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.

The lymphostins are a family of closely related pyrrolo[4,3,2-]quinoline natural products produced by and actinobacteria. Neolymphostin A was recently shown to strongly inhibit phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) in a covalent manner via conjugation to a catalytic lysine residue in the ATP-binding pocket of the enzymes, making this metabolite the first reported covalent kinase inhibitor from a bacterium. A flexible and efficient synthetic route toward these alkaloids would allow for improvements in their solubility, stability, and selectivity and help to deliver a viable drug candidate. We have since established a short synthesis to methyl 8-bromo-1,3,4,5-tetrahydropyrrolo[4,3,2-]quinoline-4-carboxylate via a conjugate addition/intramolecular Ullman reaction sequence. However, attempts to oxidize this intermediate to the pyrrolo[4,3,2-]quinoline characteristic of the lymphostins resulted in formation of either a 2-oxo-1,2-dihydropyrrolo[4,3,2-]quinoline or an unusual ,-linked tetrahydropyrroloquinoline-pyrroloquinoline heterodimer. We expect that key modifications to the tetrahydropyrroloquinoline intermediate prior to oxidation should prevent these side reactions and pave the way for the completion of the synthesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.9b01041DOI Listing
July 2019

Nature's Combinatorial Biosynthesis Produces Vatiamides A-F.

Angew Chem Int Ed Engl 2019 07 28;58(27):9027-9031. Epub 2019 May 28.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.

Hybrid type I PKS/NRPS biosynthetic pathways typically proceed in a collinear manner wherein one molecular building block is enzymatically incorporated in a sequence that corresponds to gene arrangement. In this work, genome mining combined with the use of a fluorogenic azide-based click probe led to the discovery and characterization of vatiamides A-F, three structurally diverse alkynylated lipopeptides, and their brominated analogues, from the cyanobacterium Moorea producens ASI16Jul14-2. These derive from a unique combinatorial non-collinear PKS/NRPS system encoded by a 90 kb gene cluster in which an upstream PKS cassette interacts with three separate cognate NRPS partners. This is facilitated by a series of promiscuous intermodule PKS-NRPS docking motifs possessing identical amino acid sequences. This interaction confers a new type of combinatorial capacity for creating molecular diversity in microbial systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201902571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626303PMC
July 2019

Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space.

ACS Cent Sci 2018 Dec 5;4(12):1727-1741. Epub 2018 Dec 5.

Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States.

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (-)-2()-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acscentsci.8b00747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311695PMC
December 2018

Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.

J Med Chem 2018 12 28;61(23):10463-10472. Epub 2018 Nov 28.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.

Using a novel chemistry-based assay for identifying electrophilic natural products in unprocessed extracts, we identified the PI3-kinase/mTOR dual inhibitor neolymphostin A from Salinispora arenicola CNY-486. The method further showed that the vinylogous ester substituent on the neolymphostin core was the exact site for enzyme conjugation. Tandem MS/MS experiments on PI3Kα treated with the inhibitor revealed that neolymphostin covalently modified Lys802 with a shift in mass of +306 amu, corresponding to addition of the inhibitor and elimination of methanol. The binding pose of the inhibitor bound to PI3Kα was modeled, and hydrogen-deuterium exchange mass spectrometry experiments supported this model. Against a panel of kinases, neolymphostin showed good selectivity for PI3-kinase and mTOR. In addition, the natural product blocked AKT phosphorylation in live cells with an IC of ∼3 nM. Taken together, neolymphostin is the first reported example of a covalent kinase inhibitor from the bacterial domain of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b00975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688905PMC
December 2018

Nitrosopyridine Probe To Detect Polyketide Natural Products with Conjugated Alkenes: Discovery of Novodaryamide and Nocarditriene.

ACS Chem Biol 2018 11 26;13(11):3097-3106. Epub 2018 Oct 26.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.

An optimized nitroso-based probe that facilitates the discovery of conjugated alkene-containing natural products in unprocessed extracts was developed. It chemoselectively reacts with conjugated olefins via a nitroso-Diels-Alder cyclization to yield derivatives with a distinct chromophore and an isotopically unique bromine atom that can be rapidly identified using liquid chromatography/mass spectrometry and a bioinformatics tool called MeHaloCoA (Marine Halogenated Compound Analysis). The probe is ideally employed when genome-mining techniques identify strains containing polyketide gene clusters with two or more repeating KS-AT-DH-KR-ACP domain sequences, which are required for the biosynthesis of conjugated alkenes. Comparing the reactivity and spectral properties of five brominated arylnitroso reagents with model compounds spiramycin, bufalin, rapamycin, and rifampicin led to the identification of 5-bromo-2-nitrosopyridine as the most suitable probe structure. The utility of the dienophile probe was then demonstrated in bacterial extracts. Tylactone, novodaryamide and daryamide A, piperazimycin A, and the saccharamonopyrones A and B were cleanly labeled in extracts from their respective bacterial producers, in high regioselectivity but with varying degrees of diastereoselectivity. Further application of the method led to the discovery of a new natural product called nocarditriene, containing an unprecedented epoxy-2,3,4,5-tetrahydropyridine structure, from marine-derived Nocardiopsis strain CNY-503.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschembio.8b00598DOI Listing
November 2018

The role of inter-species interactions in Salinispora specialized metabolism.

Microbiology (Reading) 2018 07 7;164(7):946-955. Epub 2018 Jun 7.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, USA.

Bacterial genome sequences consistently contain many more biosynthetic gene clusters encoding specialized metabolites than predicted by the compounds discovered from the respective strains. One hypothesis invoked to explain the cryptic nature of these gene clusters is that standard laboratory conditions do not provide the environmental cues needed to trigger gene expression. A potential source of such cues is other members of the bacterial community, which are logical targets for competitive interactions. In this study, we examined the effects of such interactions on specialized metabolism in the marine actinomycete Salinispora tropica. The results show that antibiotic activities and the concentration of some small molecules increase in the presence of co-occurring bacterial strains relative to monocultures. Some increases in antibiotic activity could be linked to nutrient depletion by the competitor as opposed to the production of a chemical cue. Other increases were correlated with the production of specific compounds by S. tropica. In particular, one interaction with a Vibrio sp. consistently induced antibiotic activity and was associated with parent ions that were unique to this interaction, although the associated compound could not be identified. This study provides insight into the metabolomic complexities of bacterial interactions and baseline information for future genome mining efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1099/mic.0.000679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152374PMC
July 2018

Discovery, Biosynthesis and Stress-Related Accumulation of Dolabradiene-Derived Defenses in Maize.

Plant Physiol 2018 04 23;176(4):2677-2690. Epub 2018 Feb 23.

Department of Plant Biology, University of California, Davis, California

Terpenoids are a major component of maize () chemical defenses that mediate responses to herbivores, pathogens, and other environmental challenges. Here, we describe the biosynthesis and elicited production of a class of maize diterpenoids, named dolabralexins. Dolabralexin biosynthesis involves the sequential activity of two diterpene synthases, -COPALYL DIPHOSPHATE SYNTHASE (ZmAN2) and KAURENE SYNTHASE-LIKE4 (ZmKSL4). Together, ZmAN2 and ZmKSL4 form the diterpene hydrocarbon dolabradiene. In addition, we biochemically characterized a cytochrome P450 monooxygenase, ZmCYP71Z16, which catalyzes the oxygenation of dolabradiene to yield the epoxides 15,16-epoxydolabrene (epoxydolabrene) and 3β-hydroxy-15,16-epoxydolabrene (epoxydolabranol). The absence of dolabradiene and epoxydolabranol in mutants under elicited conditions confirmed the in vivo biosynthetic requirement of ZmAN2. Combined mass spectrometry and NMR experiments demonstrated that much of the epoxydolabranol is further converted into 3β,15,16-trihydroxydolabrene (trihydroxydolabrene). Metabolite profiling of field-grown maize root tissues indicated that dolabralexin biosynthesis is widespread across common maize cultivars, with trihydroxydolabrene as the predominant diterpenoid. Oxidative stress induced dolabralexin accumulation and transcript expression of and in root tissues, and metabolite and transcript accumulation were up-regulated in response to elicitation with the fungal pathogens and Consistently, epoxydolabranol significantly inhibited the growth of both pathogens in vitro at 10 µg mL, while trihydroxydolabrene-mediated inhibition was specific to These findings suggest that dolabralexins have defense-related roles in maize stress interactions and expand the known chemical space of diterpenoid defenses as genetic targets for understanding and ultimately improving maize resilience.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1104/pp.17.01351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884620PMC
April 2018

Ecological implications of hypoxia-triggered shifts in secondary metabolism.

Environ Microbiol 2017 06 21;19(6):2182-2191. Epub 2017 Mar 21.

Scripps Institution of Oceanography, Center for Marine Biotechnology and Biomedicine, University of California San Diego, La Jolla, CA, USA.

Members of the actinomycete genus Streptomyces are non-motile, filamentous bacteria that are well-known for the production of biomedically relevant secondary metabolites. While considered obligate aerobes, little is known about how these bacteria respond to periods of reduced oxygen availability in their natural habitats, which include soils and ocean sediments. Here, we provide evidence that the marine streptomycete strain CNQ-525 can reduce MnO via a diffusible mechanism. We investigated the effects of hypoxia on secondary metabolite production and observed a shift away from the antibiotic napyradiomycin towards 8-amino-flaviolin, an intermediate in the napyradiomycin biosynthetic pathway. We purified 8-amino-flaviolin and demonstrated that it is reversibly redox-active (midpoint potential -474.5 mV), indicating that it has the potential to function as an endogenous extracellular electron shuttle. This study provides evidence that environmentally triggered changes in secondary metabolite production may provide clues to the ecological functions of specific compounds, and that Gram-positive bacteria considered to be obligate aerobes may play previously unrecognized roles in biogeochemical cycling through mechanisms that include extracellular electron shuttling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1462-2920.13700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481476PMC
June 2017

Thiol-Based Probe for Electrophilic Natural Products Reveals That Most of the Ammosamides Are Artifacts.

J Nat Prod 2017 01 5;80(1):126-133. Epub 2017 Jan 5.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego , La Jolla, California 92093-0204, United States.

To date, 16 members of the ammosamide family of natural products have been discovered, and except for ammosamide D each of these metabolites is characterized by an unusual chlorinated pyrrolo[4,3,2-de]quinoline skeleton. Several ammosamides have been shown to inhibit quinone reductase 2, a flavoenzyme responsible for quelling toxic oxidative species in cells or for killing cancer cells outright. Treatment of the extract from an ammosamide-producing culture (Streptomyces strain CNR-698) with a thiol-based reagent designed to label electrophilic natural products produced an ammosamide C-thiol adduct. This observation led us to hypothesize, and then demonstrate through experimentation, that all of the other ammosamides are derived from ammosamide C via nonenzymatic processes involving exposure to nucleophiles, air, and light. Like many established electrophilic natural products, reaction with the thiol probe suggests that ammosamide C is itself an electrophilic natural product. Although ammosamide C did not show substantial cytotoxicity against cancer cells, its activity against a marine Bacillus bacterial strain may reflect its ecological role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jnatprod.6b00773DOI Listing
January 2017

Thiol Probes To Detect Electrophilic Natural Products Based on Their Mechanism of Action.

ACS Chem Biol 2016 08 28;11(8):2328-36. Epub 2016 Jun 28.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego , La Jolla, California 92093, United States.

New methods are urgently needed to find novel natural products as structural leads for the development of new drugs against emerging diseases such as cancer and multiresistant bacterial infections. Here we introduce a reactivity-guided drug discovery approach for electrophilic natural products, a therapeutically relevant class of natural products that covalently modify their cellular targets, in crude extracts. Using carefully designed halogenated aromatic reagents, the process furnishes derivatives that are UV-active and highly conspicuous via mass spectrometry by virtue of an isotopically unique bromine or chlorine tag. In addition to the identification of high-value metabolites, the process facilitates the difficult task of structure elucidation by providing derivatives that are primed for X-ray crystallographic analysis. We show that a cysteine probe efficiently and chemoselectively labels enone-, β-lactam-, and β-lactone-based electrophilic natural products (parthenolide, andrographolide, wortmannin, penicillin G, salinosporamide), while a thiophenol probe preferentially labels epoxide-based electrophilic natural products (triptolide, epoxomicin, eponemycin, cyclomarin, salinamide). Using the optimized method, we were able to detect and isolate the epoxide-bearing natural product tirandalydigin from Salinispora and thereby link an orphan gene cluster to its gene product.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschembio.5b00924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295175PMC
August 2016

Sioxanthin, a novel glycosylated carotenoid, reveals an unusual subclustered biosynthetic pathway.

Environ Microbiol 2015 Jun 11;17(6):2158-71. Epub 2014 Dec 11.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA, 92093, USA.

Members of the marine actinomycete genus Salinispora constitutively produce a characteristic orange pigment during vegetative growth. Contrary to the understanding of widespread carotenoid biosynthesis pathways in bacteria, Salinispora carotenoid biosynthesis genes are not confined to a single cluster. Instead, bioinformatic and genetic investigations confirm that four regions of the Salinispora tropica CNB-440 genome, consisting of two gene clusters and two independent genes, contribute to the in vivo production of a single carotenoid. This compound, namely (2'S)-1'-(β-D-glucopyranosyloxy)-3',4'-didehydro-1',2'-dihydro-φ,ψ-caroten-2'-ol, is novel and has been given the trivial name 'sioxanthin'. Sioxanthin is a C40 -carotenoid, glycosylated on one end of the molecule and containing an aryl moiety on the opposite end. Glycosylation is unusual among actinomycete carotenoids, and sioxanthin joins a rare group of carotenoids with polar and non-polar head groups. Gene sequence homology predicts that the sioxanthin biosynthetic pathway is present in all of the Salinispora as well as other members of the family Micromonosporaceae. Additionally, this study's investigations of clustering of carotenoid biosynthetic genes in heterotrophic bacteria show that a non-clustered genome arrangement is more common than previously suggested, with nearly half of the investigated genomes showing a non-clustered architecture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1462-2920.12669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755588PMC
June 2015

Chlorizidine, a cytotoxic 5H-pyrrolo[2,1-a]isoindol-5-one-containing alkaloid from a marine Streptomyces sp.

Org Lett 2013 Mar 13;15(5):988-91. Epub 2013 Feb 13.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California-San Diego, La Jolla, California 92093-0204, USA.

Cultivation of an obligate marine Streptomyces strain has provided the cytotoxic natural product chlorizidine A. X-ray crystallographic analysis revealed that the metabolite is composed of a chlorinated 2,3-dihydropyrrolizine ring attached to a chlorinated 5H-pyrrolo[2,1-a]isoindol-5-one. The carbon stereocenter in the dihydropyrrolizine is S-configured. Remarkably, the 5H-pyrrolo[2,1-a]isoindol-5-one moiety has no precedence in the field of natural products. The presence of this ring system, which was demonstrated to undergo facile nucleophilic substitution reactions at the activated carbonyl group, is essential to the molecule's cytotoxicity against HCT-116 human colon cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol303374eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702164PMC
March 2013

Flavoenzyme-catalyzed atropo-selective N,C-bipyrrole homocoupling in marinopyrrole biosynthesis.

J Am Chem Soc 2012 Aug 18;134(30):12434-7. Epub 2012 Jul 18.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92093, United States.

Axially chiral biaryl compounds are frequently encountered in nature where they exhibit diverse biological properties. Many are biphenols that have C-C or C-O linkages installed by cytochrome P450 oxygenases that control the regio- and stereoselectivity of the intermolecular coupling reaction. In contrast, bipyrrole-coupling enzymology has not been observed. Marinopyrroles, produced by a marine-derived streptomycete, are the first 1,3'-bipyrrole natural products. On the basis of marinopyrrole's unusual bipyrrole structure, we explored its atropo-selective biosynthesis in Streptomyces sp. CNQ-418 in order to elucidate the N,C-bipyrrole homocoupling enzymology. Through a series of genetic experiments involving the discovery and heterologous expression of marinopyrrole biosynthesis genes, we report that two flavin-dependent halogenases catalyze the unprecedented homocoupling reaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ja305670fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415713PMC
August 2012

Pharmacological properties of the marine natural product marinopyrrole A against methicillin-resistant Staphylococcus aureus.

Antimicrob Agents Chemother 2011 Jul 18;55(7):3305-12. Epub 2011 Apr 18.

Skaggs School of Pharmacy and Pharmaceutical Sciences, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California 92093-0687, USA.

The ongoing spread of methicillin-resistant Staphylococcus aureus (MRSA) strains in hospital and community settings presents a great challenge to public health and illustrates the urgency of discovering new antibiotics. Marinopyrrole A is a member of a structurally novel class of compounds identified from a species of marine-derived streptomycetes with evidence of antistaphylococcal activity. We show that marinopyrrole A has potent concentration-dependent bactericidal activity against clinically relevant hospital- and community-acquired MRSA strains, a prolonged postantibiotic effect superior to that of the current first-line agents vancomycin and linezolid, and a favorable resistance profile. Marinopyrrole A showed limited toxicity to mammalian cell lines (at >20× MIC). However, its antibiotic activity against MRSA was effectively neutralized by 20% human serum. A variety of marinopyrrole analogs were isolated from culture or synthetically produced to try to overcome the inhibitory effect of serum. While many of these compounds retained potent bactericidal effect against MRSA, their activities were also inhibited by serum. Marinopyrrole A has significant affinity for plastic and may therefore have potential as a potent anti-MRSA agent in cutaneous, intracatheter, or antibiotic-lock applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.01211-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3122406PMC
July 2011

Antibacterials from the sea.

Chemistry 2010 Nov;16(42):12512-25

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, UCSD, 9500 Gilman Dr. La Jolla, CA 92093-0204, USA.

The ocean contains a host of macroscopic life in a great microbial soup. Unlike the terrestrial environment, an aqueous environment provides perpetual propinquity and blurs spatial distinctions. Marine organisms are under a persistent threat of infection by resident pathogenic microbes including bacteria, and in response they have engineered complex organic compounds with antibacterial activity from a diverse set of biological precursors. The diluting effect of the ocean drives the construction of potent molecules that are stable to harsh salty conditions. Members of each class of metabolite-ribosomal and non-ribosomal peptides, alkaloids, polyketides, and terpenes-have been shown to exhibit antibacterial activity. The sophistication and diversity of these metabolites points to the ingenuity and flexibility of biosynthetic processes in Nature. Compared with their terrestrial counterparts, antibacterial marine natural products have received much less attention. Thus, a concerted effort to discover new antibacterials from marine sources has the potential to contribute significantly to the treatment of the ever increasing drug-resistant infectious diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/chem.201001279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071975PMC
November 2010

Structures, reactivities, and antibiotic properties of the marinopyrroles A-F.

J Org Chem 2010 May;75(10):3240-50

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California 92093-0204, USA.

Cultivation of actinomycete strain CNQ-418, retrieved from a deep ocean sediment sample off the coast of La Jolla, CA, has provided marinopyrroles A-F. Sharing just 98% 16S rRNA gene sequence identity with S. sannurensis, the strain likely represents a new Streptomyces species. The metabolites contain an unusual 1,3'-bipyrrole core decorated with several chlorine and bromine substituents and possess marked antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). The congested N,C-biaryl bond establishes an axis of chirality that, for marinopyrroles A-E, is configurationally stable at room temperature. Moreover, the natural products are fashioned strictly in the M-configuration. The Paal-Knorr condensation was adapted for the synthesis of the 1,3'-bipyrrole core. Halogenation of this material with N-bromosuccinimide cleanly furnished the 4,4',5,5'-tetrahalogenated core that characterizes this class of marine-derived metabolites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo1002054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884375PMC
May 2010

Total synthesis of the ammosamides.

J Am Chem Soc 2010 Mar;132(8):2528-9

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California 92093-0204, USA.

The ammosamides A-C are chlorinated pyrrolo[4,3,2-de]quinoline metabolites isolated from the marine-derived Streptomyces strain CNR-698. The natural products, which possess a dense array of heteroatoms, were synthesized in 17-19 steps from 4-chloroisatin. That the five nitrogen atoms were introduced at the appropriate time and in a suitable oxidation state was key to the success of the total synthesis. Compared to synthetic deschloro ammosamide B, natural ammosamide B is much less susceptible to oxidative degradation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ja9106572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828514PMC
March 2010

Function-oriented biosynthesis of beta-lactone proteasome inhibitors in Salinispora tropica.

J Med Chem 2009 Oct;52(19):6163-7

Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92093, USA.

The natural proteasome inhibitor salinosporamide A from the marine bacterium Salinispora tropica is a promising drug candidate for the treatment of multiple myeloma and mantle cell lymphoma. Using a comprehensive approach that combined chemical synthesis with metabolic engineering, we generated a series of salinosporamide analogues with altered proteasome binding affinity. One of the engineered compounds is equipotent to salinosporamide A in inhibition of the chymotrypsin-like activity of the proteasome yet exhibits superior activity in the cell-based HCT-116 assay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm901098mDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771571PMC
October 2009

Marinopyrrole A target elucidation by acyl dye transfer.

J Am Chem Soc 2009 Sep;131(34):12094-6

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California 92093-0204, USA.

The targeting of marinopyrrole A to actin was identified using a fluorescent dye transfer strategy. The process began by appending a carboxylic acid terminal tag to a phenol in the natural product. The resulting probe was then studied in live cells to verify that it maintained activity comparable to marinopyrrole A. Two-color fluorescence microscopy confirmed that both unlabeled and labeled materials share comparable uptake and subcellular localization in HCT-116 cells. Subsequent immunoprecipitation studies identified actin as a putative target in HCT-116 cells, a result that was validated by mass spectral, affinity, and activity analyses on purified samples of actin. Further data analyses indicated that the dye in the marinopyrrole probe was selectively transferred to a single residue K(115), an event that did not occur with related acyl phenols and reactive labels. In this study, the combination of cell, protein, and amino acid analysis arose from a single sample of material, thereby, suggesting a means to streamline and reduce material requirements involved in mode of action studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ja903149uDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769490PMC
September 2009

Ammosamides A and B target myosin.

Angew Chem Int Ed Engl 2009 ;48(4):728-32

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0204, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.200804107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820877PMC
January 2009

The ammosamides: structures of cell cycle modulators from a marine-derived Streptomyces species.

Angew Chem Int Ed Engl 2009 ;48(4):725-7

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0204, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.200804890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819817PMC
January 2009

The marinopyrroles, antibiotics of an unprecedented structure class from a marine Streptomyces sp.

Org Lett 2008 Feb 19;10(4):629-31. Epub 2008 Jan 19.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California-San Diego, La Jolla, California 92093-0204, USA.

Cultivation of an obligate marine Streptomyces strain has furnished the marinopyrroles A and B, densely halogenated, axially chiral metabolites that contain an uncommon bispyrrole structure. X-ray analysis of marinopyrrole B showed that the natural product exists as an atropo-enantiomer with the M-configuration. Though configurationally stable at room temperature, M-(-)-marinopyrrole A can be racemized at elevated temperatures to yield the non-natural P-(+)-atropo-enantiomer. The marinopyrroles possess potent antibiotic activities against methicillin-resistant Staphylococcus aureus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol702952nDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820876PMC
February 2008

Total synthesis of (-)-heptemerone B and (-)-guanacastepene E.

J Am Chem Soc 2006 Dec;128(51):17057-62

Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720-1460, USA.

A concise, stereoselective, and convergent total synthesis of the unnatural enantiomer of the neodolastane diterpenoid heptemerone B has been completed. Saponification of (-)-heptemerone afforded (-)-guanacastepene E. The absolute stereochemistry of (-)-heptemerone B was thus established as 5-(S), the same as (-)-guanacastepene E. The longest linear sequence of the synthesis comprises 17 (18) steps from simple known starting materials. Our general synthetic approach integrates a diverse set of reactions, including an intramolecular Heck reaction to create one quaternary stereocenter and a cuprate conjugate addition for the establishment of the other. The central seven-membered ring was closed with an uncommon electrochemical oxidation, whereas the five-membered ring was formed through ring-closing metathesis. The absolute configuration of the two key building blocks was established through an asymmetric reduction and an asymmetric ene reaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ja0660507DOI Listing
December 2006

Infrared hole burning and conformational change in a borane-ammonia complex.

J Phys Chem A 2005 Sep;109(34):7714-7

Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.

The N-D stretching region in the infrared spectrum of the ammonia complex of tris-(2-methoxymethyl-phenol)-borane containing one D atom has been examined. The N-D bands have been hole burned, and the resulting spectra reveal the reorientation kinetics of the ammonia. The ammonia is hydrogen bonded with the bond distances and reorientation barrier typical of other compounds. The N-D stretching frequencies are higher than those of comparison compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jp051969iDOI Listing
September 2005

Concise synthesis of (+/-)-rhazinilam through direct coupling.

Org Lett 2005 Nov;7(23):5207-9

Department of Chemistry, University of California, Berkeley, California 94720, USA.

[reaction: see text] A concise synthesis of rhazinilam through direct, palladium-catalyzed, intramolecular coupling is described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol052033vDOI Listing
November 2005

An electrochemical approach to the guanacastepenes.

Org Lett 2005 Aug;7(16):3425-8

Center for New Directions in Organic Synthesis, Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720, USA.

An asymmetric approach toward the [6-7-5] ring system of the guanacastepenes is described. [structure: see text]
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol047387lDOI Listing
August 2005

Synthetic studies toward the guanacastepenes.

Org Lett 2003 Oct;5(22):4113-5

Center for New Directions in Organic Synthesis, Department of Chemistry, University of California-Berkeley, Berkeley, California 94720, USA.

[reaction: see text]. An asymmetric approach toward the [6-7] ring system of the guanacastepenes is described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ol035559tDOI Listing
October 2003

The total synthesis of (-)-amathaspiramide F.

Angew Chem Int Ed Engl 2002 Dec;41(23):4556-9

Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, CA 94720-1460, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/1521-3773(20021202)41:23<4556::AID-ANIE4556>3.0.CO;2-EDOI Listing
December 2002
-->