Discovery of MRSA active antibiotics using primary sequence from the human microbiome

Chu, John; Vila-Farrés, Xavier; Inoyama, Daigo; Ternei, Melinda A.; Cohen, Louis; Gordon, Emma A.; Reddy, Boojala Vijay B.; Charlop–Powers, Zachary; Zebroski, Henry; Gallardo‐Macias, Ricardo; Jaskowski, Mark; Satish, Shruthi; Park, Steven; Perlin, David S.; Freundlich, Joel S.; Brady, Sean F.

doi:10.1038/nchembio.2207

Cited by 145 publications

(168 citation statements)

References 32 publications

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“…311 Growing out of antecedent tools for comparative analysis of genetic information such as BLAST, 312 HMMER, 313 and algorithms for the detection of specific classes of gene cluster families (many of which were recently reviewed 314 ), ClusterFinder has been successfully used to identify putative gene clusters from microbiome data and led to the characterization of metabolites. 36, 315 Part of the antiSMASH platform, 316–318 ClusterFinder is a more general probabilistic algorithm used to identify BGCs of broad structural classes ranging from polysaccharides to PKs and peptides. AntiSMASH 3.0 also has algorithms to compare orphan gene clusters to a manually curated database of characterized gene clusters (ClusterBlast) and to predict substrate specificity of active sites with some metabolite structural prediction, thus reducing the manual curation necessary to link metabolites and their BGCs.…”

Section: The Untapped (Research) Potential Of the Microbiotamentioning

confidence: 99%

Natural products as mediators of disease

et al. 2017

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Humans are walking microbial ecosystems, each harboring a complex microbiome with the genetic potential to produce a vast array of natural products. Recent sequencing data suggest that our microbial inhabitants are critical for maintaining overall health. Shifts in microbial communities have been correlated to a number of diseases including infections, inflammation, cancer, and neurological disorders. Some of these clinically and diagnostically relevant phenotypes are a result of the presence of small molecules, yet we know remarkably little about their contributions to the health of individuals. Here, we review microbe-derived natural products as mediators of human disease.

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Section: The Untapped (Research) Potential Of the Microbiotamentioning

confidence: 99%

Natural products as mediators of disease

et al. 2017

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“…35 Chemical structures have been predicted from genomics, prompting synthesis of hypothetical analogs, but without reference to any initial activity. 36 While novel chemistry can be discovered in this way, these methods suffer from the limitation that, in general, the potential biological activity is only determined after the extensive labor of producing compounds derived from biosynthetic pathways.…”

Section: Discussionmentioning

confidence: 99%

Accessing chemical diversity from the uncultivated symbionts of small marine animals

et al. 2018

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Chemistry drives many biological interactions between the microbiota and host animals, yet it is often challenging to identify the chemicals involved. This poses a problem, as such small molecules are excellent sources of potential pharmaceuticals, pretested by nature for animal compatibility. We discovered anti-HIV compounds from small, marine tunicates from the Eastern Fields of Papua New Guinea. Tunicates are a reservoir for novel bioactive chemicals, yet their small size often impedes identification or even detection of the chemicals within. We solved this problem by combining chemistry, metagenomics, and synthetic biology to directly identify and synthesize the natural products. We show that these anti-HIV compounds, the divamides, are a novel family of lanthipeptides produced by symbiotic bacteria living in the tunicate. Neighboring animal colonies contain structurally related divamides that differ starkly in their biological properties, suggesting a role for biosynthetic plasticity in a native context where biological interactions take place.

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“…As an example, a terpene synthase from S. avermitilis was expressed in E. coli , resulting in the synthesis of the novel tricyclic sesquiterpene, avermitilol41. Chu et al 42. used primary sequence from the human microbiome, and thus bioinformatically predicted and chemical synthesized a new antibiotic.…”

Section: Discussionmentioning

confidence: 99%

Complete genome sequencing and antibiotics biosynthesis pathways analysis of Streptomyces lydicus 103

Nan

Ding

Luo

et al. 2017

Sci Rep

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More and more new natural products have been found in Streptomyces species, which become the significant resource for antibiotics production. Among them, Streptomyces lydicus has been known as its ability of streptolydigin biosynthesis. Herein, we present the genome analysis of S. lydicus based on the complete genome sequencing. The circular chromosome of S. lydicus 103 comprises 8,201,357 base pairs with average GC content 72.22%. With the aid of KEGG analysis, we found that S. lydicus 103 can transfer propanoate to succinate, glutamine or glutamate to 2-oxoglutarate, CO2 and L-glutamate to ammonia, which are conducive to the the supply of amino acids. S. lydicus 103 encodes acyl-CoA thioesterase II that takes part in biosynthesis of unsaturated fatty acids, and harbors the complete biosynthesis pathways of lysine, valine, leucine, phenylalanine, tyrosine and isoleucine. Furthermore, a total of 27 putative gene clusters have been predicted to be involved in secondary metabolism, including biosynthesis of streptolydigin, erythromycin, mannopeptimycin, ectoine and desferrioxamine B. Comparative genome analysis of S. lydicus 103 will help us deeply understand its metabolic pathways, which is essential for enhancing the antibiotic production through metabolic engineering.

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Discovery of MRSA active antibiotics using primary sequence from the human microbiome

Cited by 145 publications

References 32 publications

Natural products as mediators of disease

Natural products as mediators of disease

Accessing chemical diversity from the uncultivated symbionts of small marine animals

Complete genome sequencing and antibiotics biosynthesis pathways analysis of Streptomyces lydicus 103

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