Assembly and clustering of natural antibiotics guides target identification

Johnston, Chad W.; Skinnider, Michael A.; Dejong, Chris A.; Rees, Philip N.; Chen, Gregory M.; Walker, Chelsea; French, Shawn; Brown, Eric D.; Bérdy, János; Liu, Dennis Y.; Magarvey, Nathan A.

doi:10.1038/nchembio.2018

Cited by 89 publications

(91 citation statements)

References 53 publications

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“…As researchers see promise in scouring the literature and databases for orphaned antibiotics, with a hope to resurrect them as viable drug candidates, 39 promising, yet undeveloped, current drug leads, such as PTM and PTN, should remain in the pipeline.…”

Section: Discussionmentioning

confidence: 99%

In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin

Dong

Rudolf

Lin

et al. 2017

Bioorganic & Medicinal Chemistry

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Platensimycin (PTM) and platencin (PTN), two natural products and promising drug leads that target bacterial and mammalian fatty acid synthases, are known to have unfavorable pharmacokinetic properties. It is not clear, however, what the metabolic fates of PTM and PTN are and no efforts have been reported to address this key roadblock in the development of these compounds as viable drug options. Here we describe the pharmacokinetics of PTM and PTN, and reveal rapid renal clearance as the primary metabolic liability with three additional sites of chemical liability: (i) amide hydrolysis, (ii) glucuronidation, and (iii) oxidation. We determined that hydrolysis is a viable clearance mechanism in vivo and synthesized two PTM analogues to address in vivo hydrolysis. Urea- and carbamate-PTM analogues showed no detectable hydrolysis in vivo, at the expense of antibacterial activity, with no further improvement in systemic exposure. The antibacterial sulfur-containing analogues PTM D1 and PTM ML14 showed significant decreases in renal clearance. These studies set the stage for continued generation of PTM and PTN analogues in an effort to improve their pharmacokinetics while retaining or improving their biological activities.

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Section: Discussionmentioning

confidence: 99%

In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin

Dong

Rudolf

Lin

et al. 2017

Bioorganic & Medicinal Chemistry

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“…Despite declining discovery rates, genomic data now indicate the vast majority of natural products remain undiscovered (2). This observation has spurred interest in leveraging bacterial genome sequence data for natural product discovery (3)(4)(5)(6)(7)(8)(9). Several tools have been developed to integrate genomic data toward the genome-guided discovery of modular, assembly line-derived natural products, including polyketides and nonribosomal peptides, by applying the biosynthetic logic elucidated from the study of model pathways (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19).…”

mentioning

confidence: 99%

Genomic charting of ribosomally synthesized natural product chemical space facilitates targeted mining

Skinnider

Johnston

Edgar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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128

129

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Microbial natural products are an evolved resource of bioactive small molecules, which form the foundation of many modern therapeutic regimes. Ribosomally synthesized and posttranslationally modified peptides (RiPPs) represent a class of natural products which have attracted extensive interest for their diverse chemical structures and potent biological activities. Genome sequencing has revealed that the vast majority of genetically encoded natural products remain unknown. Many bioinformatic resources have therefore been developed to predict the chemical structures of natural products, particularly nonribosomal peptides and polyketides, from sequence data. However, the diversity and complexity of RiPPs have challenged systematic investigation of RiPP diversity, and consequently the vast majority of genetically encoded RiPPs remain chemical “dark matter.” Here, we introduce an algorithm to catalog RiPP biosynthetic gene clusters and chart genetically encoded RiPP chemical space. A global analysis of 65,421 prokaryotic genomes revealed 30,261 RiPP clusters, encoding 2,231 unique products. We further leverage the structure predictions generated by our algorithm to facilitate the genome-guided discovery of a molecule from a rare family of RiPPs. Our results provide the systematic investigation of RiPP genetic and chemical space, revealing the widespread distribution of RiPP biosynthesis throughout the prokaryotic tree of life, and provide a platform for the targeted discovery of RiPPs based on genome sequencing.

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“…Because the exact site of tailoring reactions is not always unambiguously predictable, PRISM generates combinatorial libraries of predicted structures to account for variability in the action of tailoring enzymes or in the permutation of monomers that forms the natural product backbone. We have additionally detailed the extension of structure prediction to ribosomally synthesized and post-translationally modified peptides (RiPPs) (13) and described the addition of a library of 257 HMMs to identify genes associated with antimicrobial resistance (14). …”

Section: Introductionmentioning

confidence: 99%

PRISM 3: expanded prediction of natural product chemical structures from microbial genomes

Skinnider

Merwin

Johnston

et al. 2017

Nucleic Acids Research

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294

220

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Microbial natural products represent a rich resource of pharmaceutically and industrially important compounds. Genome sequencing has revealed that the majority of natural products remain undiscovered, and computational methods to connect biosynthetic gene clusters to their corresponding natural products therefore have the potential to revitalize natural product discovery. Previously, we described PRediction Informatics for Secondary Metabolomes (PRISM), a combinatorial approach to chemical structure prediction for genetically encoded nonribosomal peptides and type I and II polyketides. Here, we present a ground-up rewrite of the PRISM structure prediction algorithm to derive prediction of natural products arising from non-modular biosynthetic paradigms. Within this new version, PRISM 3, natural product scaffolds are modeled as chemical graphs, permitting structure prediction for aminocoumarins, antimetabolites, bisindoles and phosphonate natural products, and building upon the addition of ribosomally synthesized and post-translationally modified peptides. Further, with the addition of cluster detection for 11 new cluster types, PRISM 3 expands to detect 22 distinct natural product cluster types. Other major modifications to PRISM include improved sequence input and ORF detection, user-friendliness and output. Distribution of PRISM 3 over a 300-core server grid improves the speed and capacity of the web application. PRISM 3 is available at http://magarveylab.ca/prism/.

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Assembly and clustering of natural antibiotics guides target identification

Cited by 89 publications

References 53 publications

In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin

In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin

Genomic charting of ribosomally synthesized natural product chemical space facilitates targeted mining

PRISM 3: expanded prediction of natural product chemical structures from microbial genomes

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