Total Synthesis and Semi-Synthetic Approaches to Analogues of Antibacterial Natural Product Althiomycin

Zarantonello, Paola; Leslie, Colin P.; Ferritto, Rafael; Kazmierski, Wieslaw M.

doi:10.1016/s0960-894x(01)00802-2

Cited by 40 publications

(23 citation statements)

References 16 publications

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“…The geometry of the aldoxime group has been shown to affect the bioactivity significantly, with the Z -isomer exhibiting > 4-fold decrease in minimum inhibitory concentration against various Streptococcus strains compared to the E -isomer. 129,189 The alm gene cluster was recently identified in Myxococcus xanthus DK897 using a genome mining approach guided by the hypothesis that 41 is NRPS-derived. 135 …”

Section: N–o Bond Forming Enzymesmentioning

confidence: 99%

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

et al. 2017

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Natural products that contain functional groups with heteroatom-heteroatom linkages (X–X, where X = N, O, S, and P) are a small yet intriguing group of metabolites. The reactivity and diversity of these structural motifs has captured the interest of synthetic and biological chemists alike. Functional groups containing X–X bonds are found in all major classes of natural products and often impart significant biological activity. This review presents our current understanding of the biosynthetic logic and enzymatic chemistry involved in the construction of X–X bond containing functional groups within natural products. Elucidating and characterizing biosynthetic pathways that generate X–X bonds could both provide tools for biocatalysis and synthetic biology, as well as guide efforts to uncover new natural products containing these structural features.

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Section: N–o Bond Forming Enzymesmentioning

confidence: 99%

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

et al. 2017

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“…SAR studies revealed that the configuration of the oxime group, the configuration at C4 of the thiazoline ring, the methoxypyrrolinone, and—to a lesser extent—the hydroxymethyl group are relevant for activity 3. 4 A previous screening of myxobacteria for novel antibiotics revealed that members of the genera Cystobacter and Myxococcus produce althiomycin 5. Although there are other described examples (e.g., saframycin), it is rather unusual to find a myxobacterial secondary metabolite that is also produced by a streptomycete 6.…”

Section: Proteins Encoded By the Althiomycin Biosynthetic Gene Clustementioning

confidence: 99%

Identification and Characterization of the Althiomycin Biosynthetic Gene Cluster in Myxococcus xanthus DK897

et al. 2011

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“…It is a heavily modified pentapeptide that inhibits protein biosynthesis by blocking the action of the peptidyl transferase [15], [16]. The X-ray crystal structure of the molecule was solved in 1974 [17] and the total chemical synthesis of althiomycin and analogues has been achieved (albeit with low efficiency) [18], [19]. However, the biosynthesis of althiomycin remained unexplored.…”

Section: Introductionmentioning

confidence: 99%

“…The potential of althiomycin as a therapeutic agent is unclear. Results indicate the drug shows low cytotoxicity; however, there are conflicting reports over the extent to which it acts as a broad spectrum agent [15], [19]. To date, the difficulties associated with chemical synthesis of althiomycin have impeded further investigations into the effectiveness of althiomycin as a drug.…”

Section: Introductionmentioning

confidence: 99%

The Insect Pathogen Serratia marcescens Db10 Uses a Hybrid Non-Ribosomal Peptide Synthetase-Polyketide Synthase to Produce the Antibiotic Althiomycin

et al. 2012

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There is a continuing need to discover new bioactive natural products, such as antibiotics, in genetically-amenable micro-organisms. We observed that the enteric insect pathogen, Serratia marcescens Db10, produced a diffusible compound that inhibited the growth of Bacillis subtilis and Staphyloccocus aureus. Mapping the genetic locus required for this activity revealed a putative natural product biosynthetic gene cluster, further defined to a six-gene operon named alb1–alb6. Bioinformatic analysis of the proteins encoded by alb1–6 predicted a hybrid non-ribosomal peptide synthetase-polyketide synthase (NRPS-PKS) assembly line (Alb4/5/6), tailoring enzymes (Alb2/3) and an export/resistance protein (Alb1), and suggested that the machinery assembled althiomycin or a related molecule. Althiomycin is a ribosome-inhibiting antibiotic whose biosynthetic machinery had been elusive for decades. Chromatographic and spectroscopic analyses confirmed that wild type S. marcescens produced althiomycin and that production was eliminated on disruption of the alb gene cluster. Construction of mutants with in-frame deletions of specific alb genes demonstrated that Alb2–Alb5 were essential for althiomycin production, whereas Alb6 was required for maximal production of the antibiotic. A phosphopantetheinyl transferase enzyme required for althiomycin biosynthesis was also identified. Expression of Alb1, a predicted major facilitator superfamily efflux pump, conferred althiomycin resistance on another, sensitive, strain of S. marcescens. This is the first report of althiomycin production outside of the Myxobacteria or Streptomyces and paves the way for future exploitation of the biosynthetic machinery, since S. marcescens represents a convenient and tractable producing organism.

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Total Synthesis and Semi-Synthetic Approaches to Analogues of Antibacterial Natural Product Althiomycin

Cited by 40 publications

References 16 publications

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

Identification and Characterization of the Althiomycin Biosynthetic Gene Cluster in Myxococcus xanthus DK897

The Insect Pathogen Serratia marcescens Db10 Uses a Hybrid Non-Ribosomal Peptide Synthetase-Polyketide Synthase to Produce the Antibiotic Althiomycin

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