Branimycins B and C, Antibiotics Produced by the Abyssal Actinobacterium Pseudonocardia carboxydivorans M-227

Abstract

family of macrolide antibiotics known as nargenicins, 30 which exhibit antimicrobial activity mainly against Staph-31 ylococcus aureus. Nargenicins and branimycins have a tricyclic 32 structure with either a 9-or 10-membered lactone ring and 33 contain a unique ether bridge. In 1977, the first members of the 34 nargenicin family were isolated by Pfizer and Upjohn after the 35 aerobic fermentation of Nocardia argentinensis ATCC 31306. 36 This family of compounds and their antibacterial activity were 37 later patented, 1 and the structure of one of them, nargenicin 38 A1, was elucidated.2 Although it showed antibacterial activity in 39 vitro, this was restricted to Gram-positive bacteria, particularly 40 methicillin-resistant S. aureus (MRSA). It was also described 41 that nargenicin A1 induces cell differentiation and can be used, 42 therefore, as a possible treatment for neoplastic diseases. 43The first branimycin (1) was isolated in 1998 from the 44 Actinomycete GW 60/1571 and its structure determined by the 45

Biosynthesis and Ether‐Bridge Formation in Nargenicin Macrolides

“…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.…”

“…[5][6][7] Indeed, several nargenicin-like antibiotics exist, all of which have ar are oxa-bridged decalin core as ak ey structural feature (Figure 1; see Figure S1 in the Supporting Information for nargenicin family compounds). [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.…”

The Nargenicin Family of Oxa‐Bridged Macrolide Antibiotics

“…Other related molecules including nodusmicin ( 11 ), lustromycin ( 13 ), streptoseomycin ( 14 ), luminamicin and coloradocin ( 12 ) have also been identified; the latter two of which were subsequently found to be identical . Interestingly, almost 30 years after the initial discovery of 1 , the branimycins ( 4–7 ) were identified and these are the only members of the group with a 9‐membered macrolactone ring . To date, nargenicin family antibiotics have been isolated from a range of bacterial species including Pseudonocardia, Saccharothrix , Actinoplanes , Nocardioides, Saccharopolyspora and Streptomyces species, all of which are members of the Actinobacteria, a well‐known powerhouse for natural product biosynthesis …”

Biosynthesis and Ether‐Bridge Formation in Nargenicin Macrolides

“…[5][6][7] Indeed, several nargenicin-like antibiotics exist, all of which have a rare oxa-bridged decalin core as a key structural feature (Figure 1, see Figure S1 for nargenicin family compounds). [8][9][10][11] While members of this family have been isolated from actinomycetes across a range of environments and geographic locations, the genetic basis for the production of nargenicin has remained unknown for almost 40 years. [6,[12][13][14] Also undefined has been the basis for the formation of the ether bridge in these compounds, although P450 hydroxylases have previously been suggested to be involved.…”

“…Although 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 the latter producing organisms are not yet publicly available, future sequencing of these organisms will allow for a comprehensive comparison of these PKS biosynthetic gene clusters. Here, we have shown for the first time that a dedicated bacterial dioxygenase is essential for ether bridge formation.…”