The orthosomycins, a new family of antibiotics

Wright, Derek E.

doi:10.1016/0040-4020(79)80046-0

Cited by 130 publications

(60 citation statements)

References 52 publications

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“…Avilamycin A is currently used as a growth promoter in animal feed, but the European Community decided to prohibit its further use beginning in January of 2006. Like other orthosomycins, avilamycin A inhibits the growth of multidrug-resistant grampositive bacteria (29). The orthosomycin evernimicin (also called SCH27899 or ziracin) is structurally very similar to avilamycin A.…”

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“…It was producing avilamycin derivatives, named gavibamycin A1 and A3, without a methoxy group at the orsellinic acid moiety. Structural features common to members of the orthosomycin class of antibiotics produced by various actinomycetes are a terminal dichloroisoeverninic acid unit, several deoxysugars, and an eurekanate moiety associated by an unique orthoester linkage (29). The eurekanate moiety belongs to an important class of carbohydrates, the branched-chain sugars, containing a two-carbon side chain at position C4.…”

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Genes Involved in Formation and Attachment of a Two-Carbon Chain as a Component of Eurekanate, a Branched-Chain Sugar Moiety of Avilamycin A

Treede¹,

Hauser

Mühlenweg

et al. 2005

Appl Environ Microbiol

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Eurekanate belongs to the important class of branched-chain carbohydrates present in a wide variety of natural sources. It is a component of avilamycin A, a potent inhibitor of bacterial protein synthesis targeting the 50S ribosomal subunit. The present work provides experimental proof for the function of two genes of the avilamycin biosynthetic gene cluster, aviB1 and aviO2, that are both involved in avilamycin structure modification. The functions of both genes were identified by gene inactivation experiments and nuclear magnetic resonance analyses of extracts produced by the mutants. We suggest that both AviO2 and AviB1 are involved in the biosynthesis of eurekanate within avilamycin biosynthesis. Moreover, two other genes (aviO1 and aviO3) have been inactivated, resulting in a breakdown of avilamycin production in the mutants ITO1 and ITO3, which clearly shows the essential role of both enzymes in avilamycin biosynthesis. The exact functions of both aviO1 and aviO3 remained unknown.

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Genes Involved in Formation and Attachment of a Two-Carbon Chain as a Component of Eurekanate, a Branched-Chain Sugar Moiety of Avilamycin A

Treede¹,

Hauser

Mühlenweg

et al. 2005

Appl Environ Microbiol

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“…1), which are produced by Streptomyces viridochromogenes Tü57, are oligosaccharide antibiotics and belong to the orthosomycin group of antibiotics (10). Avilamycins as well as other important members of the orthosomycins contain a dichloroisoeverninic acid moiety, as well as one or more orthoester linkages which are associated with carbohydrate residues (35). The compound SCH27899 shows excellent activity against gram-positive bacteria (22,32) and is presently being tested for possible use against human infectious diseases (31,37).…”

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Cloning of an avilamycin biosynthetic gene cluster from Streptomyces viridochromogenes Tü57

et al. 1997

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A 65-kb region of DNA from Streptomyces viridochromogenes Tü57, containing genes encoding proteins involved in the biosynthesis of avilamycins, was isolated. The DNA sequence of a 6.4-kb fragment from this region revealed four open reading frames (ORF1 to ORF4), three of which are fully contained within the sequenced fragment. The deduced amino acid sequence of AviM, encoded by ORF2, shows 37% identity to a 6-methylsalicylic acid synthase from Penicillium patulum. Cultures of S. lividans TK24 and S. coelicolor CH999 containing plasmids with ORF2 on a 5.5-kb PstI fragment were able to produce orsellinic acid, an unreduced version of 6-methylsalicylic acid. The amino acid sequence encoded by ORF3 (AviD) is 62% identical to that of StrD, a dTDP-glucose synthase from S. griseus. The deduced amino acid sequence of AviE, encoded by ORF4, shows 55% identity to a dTDP-glucose dehydratase (StrE) from S. griseus. Gene insertional inactivation experiments of aviE abolished avilamycin production, indicating the involvement of aviE in the biosynthesis of avilamycins.The avilamycins (Fig. 1), which are produced by Streptomyces viridochromogenes Tü57, are oligosaccharide antibiotics and belong to the orthosomycin group of antibiotics (10). Avilamycins as well as other important members of the orthosomycins contain a dichloroisoeverninic acid moiety, as well as one or more orthoester linkages which are associated with carbohydrate residues (35). The compound SCH27899 shows excellent activity against gram-positive bacteria (22,32) and is presently being tested for possible use against human infectious diseases (31, 37). Avilamycins inhibit the growth of grampositive bacteria, and avilamycin A is a translation inhibitor binding to the 30S ribosomal subunit (34), but the exact mode of action of the avilamycins is not known. Avilamycins are used as an additive for animal breeding (MaxusG; Eli Lilly, Bad Homburg, Germany).Few genetic studies have been carried out on the biosynthesis of orthosomycins. In 1992, Bergh and Uhlen (5) described the cloning and analysis of a polyketide synthase encoding gene cluster of S. curacoi, the producer of curamycin. The isolated gene cluster may be involved in the biosynthesis of curamycin or possibly in the biosynthesis of a spore pigment. Besides polyketide synthase genes, no other genes of this cluster were described. We recently reported a PCR method to amplify gene fragments coding for deoxynucleoside diphosphate (dNDP)-glucose 4,6-dehydratases (11), which are involved in the formation of 6-deoxyhexose moieties of different antibiotics (24). A PCR fragment was obtained by using chromosomal DNA from S. viridochromogenes Tü57 as the template. The deduced amino acid sequence of the fragment revealed similarity to known dNDP-glucose dehydratases (11). We have now used this PCR fragment as a probe to screen a cosmid library. On a cosmid hybridizing to the probe, three genes (aviD, aviE, and aviM) were detected. The disruption of aviE affected avilamycin production. Expression of the multifunctional...

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“…M. carbonacea var. africana produces fourteen previously described everninomicin congeners (31)(32)(33)(34). Before genetic manipulation, we assessed which everninomicin congeners are produced by M. carbonacea var.…”

Section: Resultsmentioning

confidence: 99%

Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily

McCulloch

McCranie

Smith

et al. 2015

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

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Orthosomycins are oligosaccharide antibiotics that include avilamycin, everninomicin, and hygromycin B and are hallmarked by a rigidifying interglycosidic spirocyclic ortho-δ-lactone (orthoester) linkage between at least one pair of carbohydrates. A subset of orthosomycins additionally contain a carbohydrate capped by a methylenedioxy bridge. The orthoester linkage is necessary for antibiotic activity but rarely observed in natural products. Orthoester linkage and methylenedioxy bridge biosynthesis require similar oxidative cyclizations adjacent to a sugar ring. We have identified a conserved group of nonheme iron, α-ketoglutarate-dependent oxygenases likely responsible for this chemistry. High-resolution crystal structures of the EvdO1 and EvdO2 oxygenases of everninomicin biosynthesis, the AviO1 oxygenase of avilamycin biosynthesis, and HygX of hygromycin B biosynthesis show how these enzymes accommodate large substrates, a challenge that requires a variation in metal coordination in HygX. Excitingly, the ternary complex of HygX with cosubstrate α-ketoglutarate and putative product hygromycin B identified an orientation of one glycosidic linkage of hygromycin B consistent with metal-catalyzed hydrogen atom abstraction from substrate. These structural results are complemented by gene disruption of the oxygenases evdO1 and evdMO1 from the everninomicin biosynthetic cluster, which demonstrate that functional oxygenase activity is critical for antibiotic production. Our data therefore support a role for these enzymes in the production of key features of the orthosomycin antibiotics.antibiotic biosynthesis | oxidative cyclization | crystal structure | nonheme iron α-ketoglutarate-dependent oxygenases

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The orthosomycins, a new family of antibiotics

Cited by 130 publications

References 52 publications

Genes Involved in Formation and Attachment of a Two-Carbon Chain as a Component of Eurekanate, a Branched-Chain Sugar Moiety of Avilamycin A

Genes Involved in Formation and Attachment of a Two-Carbon Chain as a Component of Eurekanate, a Branched-Chain Sugar Moiety of Avilamycin A

Cloning of an avilamycin biosynthetic gene cluster from Streptomyces viridochromogenes Tü57

Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily

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