Nodusmicin: The structure of a new antibiotic

Whaley, H. A.; Chidester, C. G.; Mizsak, S. A.; Wnuk, R. J.

doi:10.1016/s0040-4039(00)78737-5

Cited by 56 publications

(26 citation statements)

References 4 publications

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“…In conclusion, we have revealed the complete biosynthetic locus for 1,agene cluster that has remained hidden for almost four decades.W eh ave shown that the nar locus is solely responsible for the production of 1 and have identified narlike gene clusters from other actinomycetes,n ot previously considered to produce nargenicin-like compounds.A lthough only four currently sequenced genomes from Nocardia and Streptomyces species contain nargenicin-like gene clusters, nargenicin-family antibiotics have been also found from Pseudonocardia, Saccharothrix, Actinoplanes, Nocardioides, and Saccharopolyspora species. [8,11,12,38] While genomes of these organisms are not yet publicly available,f uture sequencing of these organisms will allow for acomprehensive comparison of these PKS biosynthetic gene clusters.Here,we have shown, for the first time,t hat ad edicated bacterial dioxygenase is essential for ether-bridge formation. Comparison of nar-like genomic loci has allowed for the identification of essential genes for the production of these macrocyclic, oxa-bridge polyketides.The nar biosynthetic locus uncovered here appears to provide ab lueprint for the biosynthesis of members of this molecular family,a nd this work paves the way for heterologous expression and biosynthetic engineering studies on this group of potent, narrow-spectrum antibiotics to derive the next generation of nargenicin-like molecules.…”

Section: Angewandte Chemiementioning

confidence: 99%

“…[8][9][10][11] While members of this family have been isolated from actinomycetes across ar ange of environments and geographic locations,t he genetic basis for the production of nargenicin has remained unknown for almost 40 years. [6,[12][13][14] Them ode of formation of the ether bridge in these compounds has also remained undefined, although P450 hydroxylases have previously been suggested to be involved. [10] Herein, we have identified the genetic basis for nargenicin biosynthesis in ah uman pathogenic Nocardia isolate and show that the nargenicin biosynthetic gene cluster is rare among sequenced bacteria.…”

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confidence: 99%

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Biosynthesis and Ether‐Bridge Formation in Nargenicin Macrolides

et al. 2019

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The nargenicin family of antibiotics are macrolides containing ar are ether-bridged cis-decalin motif.S everal of these compounds are highly active against multi-drug resistant organisms.D espite the identification of the first members of this family almost 40 years ago,t he genetic basis for the production of these molecules and the enzyme responsible for formation of the oxabridge,remain unknown. Here,the 85 kb nargenicin biosynthetic gene cluster was identified from ah uman pathogenic Nocardia arthritidis isolate and this locus is solely responsible for nargenicin production. Further investigation of this locus revealed ap utative iron-a-ketoglutarate-dependent dioxygenase,w hichw as found to be responsible for the formation of the ether bridge from the newly identified deoxygenated precursor,8 ,13-deoxynargenicin. Uncovering the nargenicin biosynthetic locus provides amolecular basis for the rational bioengineering of these interesting antibiotic macrolides. Figure 1. A) Comparison of HPLC traces of N. arthritidis AUSMDU00012717 extract with authenticn argenicin A1 standard at 265 nm. B) Structure of nargenicin A1.[*] Dr.

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Section: Angewandte Chemiementioning

confidence: 99%

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confidence: 99%

Biosynthesis and Ether‐Bridge Formation in Nargenicin Macrolides

et al. 2019

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“…[9][10][11] During this same period of time, othern argenicin antibiotics were identified including 18-deoxynargenicin A1 (2), [12] nargenicin C1 (3), [13] and nargenicin B1 (8), B2 (9)a nd B3 (10); [14] which differ only in their methylation and oxygenation patterns. Other related molecules including nodusmicin (11), [15,16] lustromycin ( 13), [17] streptoseomycin (14), [18] luminamicin [19] and coloradocin (12) [20] have also been identified;t he latter two of which were subsequently found to be identical. [21] Interestingly,a lmost3 0y ears after the initial discoveryo f1,t he branimycins (4-7)w ere identified and these are the only members of the group with a 9-membered macrolactone ring.…”

Section: The Nargenicin Antibioticsmentioning

confidence: 99%

The Nargenicin Family of Oxa‐Bridged Macrolide Antibiotics

Pidot

Rizzacasa

2019

Chemistry A European J

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The nargenicin family of antibiotic macrolides comprise a group of bacterial natural products with a rare ether bridged cis‐decalin moiety and a narrow spectrum of activity. Most family members were identified almost four decades ago and were placed on the shelf due to the numbers of broad‐spectrum compounds available at the time. However, in light of rising rates of antimicrobial resistance, there has been a renewed interest in the use of narrow‐spectrum antimicrobials. Here, we review the history of this family of compounds, including synthetic approaches, and highlight the recently uncovered genetic basis for nargenicin production. Given the renewed pharmaceutical interest in these compounds, we also investigate structure–activity relationships among these molecules, with a view to the future development of members of this unusual antibiotic family.

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“…1) is a member of a class of saturated alicyclic polyketides containing a characteristic cis-fused octalin ring system. Structurally, it is closely related to nodusmicin [8]. Nargenicin A 1 was first isolated as antibioticum CP-47,444 from cultures of N. argentinensis in 1977 [6].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Engineering of Nocardia sp. CS682 for Enhanced Production of Nargenicin A1

Maharjan

Koju

Lee

et al. 2011

Appl Biochem Biotechnol

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A number of secondary metabolites having therapeutic importance have been reported from the genus Nocardia. One of the polyketide antibiotic compounds isolated from Nocardia is nargenicin A(1). Recently, nargenicin A(1) has been isolated from Nocardia sp. CS682, a new Nocardia strain isolated from soil in Jeonnam, South Korea. It possesses strong antibacterial activity against methicillin-resistant Staphylococcus aureus. In this study, we applied a metabolic engineering approach based on recombinant DNA technology in order to boost the production of nargenicin A(1) from Nocardia sp. CS682. Initially, we optimized the transformation of this new strain by electroporation method. Heterologous expression of S-adenosylmethionine synthetase (MetK1-sp) in Nocardia sp. CS682 enhanced the production of nargenicin A(1) by about 2.8 times due to transcriptional activation of biosynthetic genes as revealed by reverse transcription polymerase chain reaction analysis. Similarly, expression of acetyl-CoA carboxylase genes improved nargenicin A(1) production by about 3.8 times in Nocardia sp. ACC18 compared to that in Nocardia sp. CS682 and Nocardia sp. NV18 by increasing precursor pool. Thus, enhanced production of nargenicin A(1) from Nocardia sp. CS682 can be achieved by expression of transcriptional activator genes and precursor genes from Streptomyces strains.

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Nodusmicin: The structure of a new antibiotic

Cited by 56 publications

References 4 publications

Biosynthesis and Ether‐Bridge Formation in Nargenicin Macrolides

Biosynthesis and Ether‐Bridge Formation in Nargenicin Macrolides

The Nargenicin Family of Oxa‐Bridged Macrolide Antibiotics

Metabolic Engineering of Nocardia sp. CS682 for Enhanced Production of Nargenicin A1

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