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1.
Chem Rev ; 122(18): 14815-14841, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-36006409

RESUMO

Biosynthetic mechanisms of natural products primarily depend on systems of protein catalysts. However, within the field of biosynthesis, there are cases in which the inherent chemical reactivity of metabolic intermediates and substrates evades the involvement of enzymes. These reactions are difficult to characterize based on their reactivity and occlusion within the milieu of the cellular environment. As we continue to build a strong foundation for how microbes and higher organisms produce natural products, therein lies a need for understanding how protein independent or nonenzymatic biosynthetic steps can occur. We have classified such reactions into four categories: intramolecular, multicomponent, tailoring, and light-induced reactions. Intramolecular reactions is one of the most well studied in the context of biomimetic synthesis, consisting of cyclizations and cycloadditions due to the innate reactivity of the intermediates. There are two subclasses that make up multicomponent reactions, one being homologous multicomponent reactions which results in dimeric and pseudodimeric natural products, and the other being heterologous multicomponent reactions, where two or more precursors from independent biosynthetic pathways undergo a variety of reactions to produce the mature natural product. The third type of reaction discussed are tailoring reactions, where postmodifications occur on the natural products after the biosynthetic machinery is completed. The last category consists of light-induced reactions involving ecologically relevant UV light rather than high intensity UV irradiation that is traditionally used in synthetic chemistry. This review will cover recent nonenzymatic biosynthetic mechanisms and include sources for those reviewed previously.


Assuntos
Produtos Biológicos , Produtos Biológicos/química , Vias Biossintéticas , Catálise , Ciclização , Reação de Cicloadição
2.
J Am Chem Soc ; 142(33): 14158-14168, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32697091

RESUMO

Bacterial natural products have inspired the development of numerous antibiotics in use today. As resistance to existing antibiotics has become more prevalent, new antibiotic lead structures and activities are desperately needed. An increasing number of natural product biosynthetic gene clusters, to which no known molecules can be assigned, are found in genome and metagenome sequencing data. Here we access structural information encoded in this underexploited resource using a synthetic-bioinformatic natural product (syn-BNP) approach, which relies on bioinformatic algorithms followed by chemical synthesis to predict and then produce small molecules inspired by biosynthetic gene clusters. In total, 157 syn-BNP cyclic peptides inspired by 96 nonribosomal peptide synthetase gene clusters were synthesized and screened for antibacterial activity. This yielded nine antibiotics with activities against ESKAPE pathogens as well as Mycobacterium tuberculosis. Not only are antibiotic-resistant pathogens susceptible to many of these syn-BNP antibiotics, but they were also unable to develop resistance to these antibiotics in laboratory experiments. Characterized modes of action for these antibiotics include cell lysis, membrane depolarization, inhibition of cell wall biosynthesis, and ClpP protease dysregulation. Increasingly refined syn-BNP-based explorations of biosynthetic gene clusters should allow for more rapid identification of evolutionarily inspired bioactive small molecules, in particular antibiotics with diverse mechanism of actions that could help confront the imminent crisis of antimicrobial resistance.


Assuntos
Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , Biologia Computacional , Mycobacterium tuberculosis/efeitos dos fármacos , Algoritmos , Antibacterianos/síntese química , Antibacterianos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular
3.
Cell Host Microbe ; 26(2): 273-282.e7, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31378678

RESUMO

Despite evidence linking the human microbiome to health and disease, how the microbiota affects human physiology remains largely unknown. Microbiota-encoded metabolites are expected to play an integral role in human health. Therefore, assigning function to these metabolites is critical to understanding these complex interactions and developing microbiota-inspired therapies. Here, we use large-scale functional screening of molecules produced by individual members of a simplified human microbiota to identify bacterial metabolites that agonize G-protein-coupled receptors (GPCRs). Multiple metabolites, including phenylpropanoic acid, cadaverine, 9-10-methylenehexadecanoic acid, and 12-methyltetradecanoic acid, were found to interact with GPCRs associated with diverse functions within the nervous and immune systems, among others. Collectively, these metabolite-receptor pairs indicate that diverse aspects of human health are potentially modulated by structurally simple metabolites arising from primary bacterial metabolism.


Assuntos
Bactérias/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Microbiota/imunologia , Microbiota/fisiologia , Receptores Acoplados a Proteínas G/agonistas , Proteínas Angiogênicas/agonistas , Animais , Cadaverina/metabolismo , Cadaverina/farmacologia , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Fermentação , Vida Livre de Germes , Agonistas dos Receptores Histamínicos , Humanos , Sistema Imunitário , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Propionatos/metabolismo , Propionatos/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/efeitos dos fármacos , Receptores de Neurotransmissores/agonistas
4.
Cell Host Microbe ; 23(6): 725-736, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29902438

RESUMO

Natural products have long played a pivotal role in the development of therapeutics for a variety of diseases. Traditionally, soil and marine environments have provided a rich reservoir from which diverse chemical scaffolds could be discovered. Recently, the human microbiome has been recognized as a promising niche from which secondary metabolites with therapeutic potential have begun to be isolated. In this Review, we address how the expansive history of identifying bacterial natural products in other environments is informing the approaches being brought to bear on the study of the human microbiota. We also touch on how these tools can lead to insights about microbe-microbe and host-microbe interactions and help generate biological hypotheses that may lead to developments of new therapeutic modalities.


Assuntos
Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Microbiota/fisiologia , Antibacterianos/metabolismo , Bactérias/genética , Bactérias/metabolismo , Humanos , Indóis/metabolismo , Metabolômica , Metagenômica , Interações Microbianas , Microbiota/genética , Família Multigênica , Peptídeos Cíclicos/metabolismo , Ácido Pirrolidonocarboxílico/metabolismo , Tiazolidinas/metabolismo
5.
Cell Chem Biol ; 23(12): 1444-1446, 2016 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-28009976

RESUMO

In this issue of Cell Chemical Biology, Jordan and Moore (2016) present a thorough biosynthetic analysis of ammosamides, a bacterial natural product. The work highlights the previously unknown overlap between two natural products families: pyrroloquinoline alkaloids and ribosomally synthesized posttranslationally modified peptides (RiPPs).

6.
J Am Chem Soc ; 138(7): 2383-8, 2016 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-26824832

RESUMO

Discoipyrroles A-D (DPA-DPD) are recently discovered natural products produced by the marine bacterium Bacillus hunanensis that exhibit anticancer properties in vitro. Initial biosynthetic studies demonstrated that DPA is formed in the liquid fermentation medium of B. hunanensis from three secreted metabolites through an unknown but protein-independent mechanism. The increased identification of natural products that depend on non-enzymatic steps creates a significant need to understand how these different reactions can occur. In this work, we utilized (15)N-labeled starting materials and continuous high-sensitivity (1)H-(15)N HMBC NMR spectroscopy to resolve scarce reaction intermediates of the non-enzymatic discoipyrrole reaction as they formed in real time. This information guided supplemental experiments using (13)C- and (18)O-labeled materials to elucidate the details of DPA's non-enzymatic biosynthesis, which features a highly concerted pyrrole formation and necessary O2-mediated oxidation. We have illustrated a novel way of using isotopically enhanced two-dimensional NMR spectroscopy to interrogate reaction mechanisms as they occur. In addition, these findings add to our growing knowledge of how multicomponent non-enzymatic reactions can occur through inherently reactive bacterial metabolites.


Assuntos
Produtos Biológicos/síntese química , Pirrolidinonas/síntese química , Bacillus/química , Bacillus/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirrolidinonas/química , Pirrolidinonas/metabolismo
7.
Biol Blood Marrow Transplant ; 21(4): 632-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25576425

RESUMO

Natural killer (NK) cell immunotherapy as a cancer treatment shows promise, but expanding NK cells consistently from a small fraction (∼ 5%) of peripheral blood mononuclear cells (PBMCs) to therapeutic amounts remains challenging. Most current ex vivo expansion methods use co-culture with feeder cells (FC), but their use poses challenges for wide clinical application. We developed a particle-based NK cell expansion technology that uses plasma membrane particles (PM-particles) derived from K562-mbIL15-41BBL FCs. These PM-particles induce selective expansion of NK cells from unsorted PBMCs, with NK cells increasing 250-fold (median, 35; 10 donors; range, 94 to 1492) after 14 days of culture and up to 1265-fold (n = 14; range, 280 to 4426) typically after 17 days. The rate and efficiency of NK cell expansions with PM-particles and live FCs are comparable and far better than stimulation with soluble 41BBL, IL-15, and IL-2. Furthermore, NK cells expand selectively with PM-particles to 86% (median, 35; range, 71% to 99%) of total cells after 14 days. The extent of NK cell expansion and cell content was PM-particle concentration dependent. These NK cells were highly cytotoxic against several leukemic cell lines and also against patient acute myelogenous leukemia blasts. Phenotype analysis of these PM-particle-expanded NK cells was consistent with an activated cytotoxic phenotype. This novel NK cell expansion methodology has promising clinical therapeutic implications.


Assuntos
Proliferação de Células , Micropartículas Derivadas de Células/imunologia , Imunidade Celular , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/imunologia , Técnicas de Cultura de Células , Feminino , Células HL-60 , Humanos , Células K562 , Masculino , Fatores de Tempo
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