The Chemistry and Biology of Bactobolin: A 10-Year Collaboration with Natural Product Chemist Extraordinaire Jon Clardy

Greenberg, E. Peter; Chandler, Josephine R.; Seyedsayamdost, Mohammad R.

doi:10.1021/acs.jnatprod.9b01237

Cited by 18 publications

(10 citation statements)

References 57 publications

(117 reference statements)

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“…A densely substituted bicyclic lactone framework is a common feature of all known members of the bactobolin family, bactobolins A–I, , and also of recently discovered cryptic metabolites acybolins A–I (Figure ). The dichloromethyl group differentiates 1 from the closely related natural product (+)-actinobolin ( 2 , Figure ), which shows similar but less potent biological activity than 1 . , All previous efforts to modulate the biological properties of (−)-bactobolin A by semisynthetic modifications supported the importance of the l -alanine residue , and the dichloromethyl group in potency of 1 . ,, Although these studies did not yield more active analogs, the insight provided by the recently determined cocrystal structure of 1 within the bacterial ribosome might allow for a rational design of new synthetic analogs.…”

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confidence: 99%

Stereocontrolled Synthesis of (−)-Bactobolin A

et al. 2020

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A stereoselective synthesis of the ribosome-binding antitumor antibiotic (−)-bactobolin A is reported. The presented approach makes effective use of (−)-quinic acid as a chiral pool starting material and substrate stereocontrol to establish the five contiguous stereocenters of (−)-bactobolin A. The key steps of the synthesis include a stereoselective vinylogous aldol reaction to introduce the unusual dichloromethyl substituent, a completely diastereoselective rhodium(II)-catalyzed C–H amination reaction to set the configuration of the axial amine, and an intramolecular alkoxycarbonylation to build the bicyclic lactone framework. The developed synthetic route was used to prepare 90 mg of (−)-bactobolin A trifluoroacetate in 10% overall yield.

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confidence: 99%

Stereocontrolled Synthesis of (−)-Bactobolin A

et al. 2020

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“…The three structurally related metabolites are produced by the same BGC. ,, Acybolins have been proposed to be the prodrug form of bactobolins. Both sets of compounds display antimicrobial activity, inhibiting the growth of a variety of bacterial species, and acybolins appear to play an additional role in QS signaling. − Bactobolins were also shown to dysregulate protein synthesis in C. elegans during Burkholderia infection, indicating that they can directly mediate host–pathogen interactions.…”

Section: Resultsmentioning

confidence: 99%

Metabolomics Analysis of Bacterial PathogenBurkholderia thailandensisand Mammalian Host Cells in Co-culture

et al. 2022

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The Tier 1 HHS/USDA Select Agent Burkholderia pseudomallei is a bacterial pathogen that is highly virulent when introduced into the respiratory tract and intrinsically resistant to many antibiotics. Transcriptomic- and proteomic-based methodologies have been used to investigate mechanisms of virulence employed by B. pseudomallei and Burkholderia thailandensis, a convenient surrogate; however, analysis of the pathogen and host metabolomes during infection is lacking. Changes in the metabolites produced can be a result of altered gene expression and/or post-transcriptional processes. Thus, metabolomics complements transcriptomics and proteomics by providing a chemical readout of a biological phenotype, which serves as a snapshot of an organism’s physiological state. However, the poor signal from bacterial metabolites in the context of infection poses a challenge in their detection and robust annotation. In this study, we coupled mammalian cell culture-based metabolomics with feature-based molecular networking of mono- and co-cultures to annotate the pathogen’s secondary metabolome during infection of mammalian cells. These methods enabled us to identify several key secondary metabolites produced by B. thailandensis during infection of airway epithelial and macrophage cell lines. Additionally, the use of in silico approaches provided insights into shifts in host biochemical pathways relevant to defense against infection. Using chemical class enrichment analysis, for example, we identified changes in a number of host-derived compounds including immune lipids such as prostaglandins, which were detected exclusively upon pathogen challenge. Taken together, our findings indicate that co-culture of B. thailandensis with mammalian cells alters the metabolome of both pathogen and host and provides a new dimension of information for in-depth analysis of the host–pathogen interactions underlying Burkholderia infection.

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“…6 The high level of selectivity and stereocontrol afforded by enzymes decreases the need for intermediate protecting/deprotection steps that are often necessary to achieve the same stereospecific product with traditional synthetic techniques. 7,8 Recent efforts have yielded impressive improvements in the biocatalysis toolbox, with de novo designed and evolved biocatalysts mediating the Kemp elimination 9 and Diels–Alder 10 reactions and playing central roles in chemical syntheses, such as the production of S -adenosyl- l -methionine (SAM) analogs. 11 However, despite major advances in the fields of metabolic and protein engineering, biocatalysts catalyze comparatively few transformations compared to the portfolio of chemically catalyzed reactions.…”

Section: Introductionmentioning

confidence: 99%