Organization of the genes encoding the biosynthesis of actagardine and engineering of a variant generation system

Boakes, Steven; Cortés, Jesús M.; Appleyard, Antony N.; Rudd, Brian A. M.; Dawson, Michael J.

doi:10.1111/j.1365-2958.2009.06708.x

Cited by 61 publications

(59 citation statements)

References 36 publications

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“…Libraries of new Antibiotic discovery in the twenty-first century S Donadio et al molecules have been obtained, many of which, as in the examples of actagardine 50 and thiocillin, 51 retained antibiotic activities comparable with those of the parent molecule.…”

Section: Improved Variants From Microbial Sourcesmentioning

confidence: 99%

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Donadio¹,

Maffioli²,

Monciardini³

et al. 2010

J Antibiot

224

126

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New antibiotics are necessary to treat microbial pathogens that are becoming increasingly resistant to available treatment. Despite the medical need, the number of newly approved drugs continues to decline. We offer an overview of the pipeline for new antibiotics at different stages, from compounds in clinical development to newly discovered chemical classes. Consistent with historical data, the majority of antibiotics under clinical development are natural products or derivatives thereof. However, many of them also represent improved variants of marketed compounds, with the consequent risk of being only partially effective against the prevailing resistance mechanisms. In the discovery arena, instead, compounds with promising activities have been obtained from microbial sources and from chemical modification of antibiotic classes other than those in clinical use. Furthermore, new natural product scaffolds have also been discovered by ingenious screening programs. After providing selected examples, we offer our view on the future of antibiotic discovery.

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Section: Improved Variants From Microbial Sourcesmentioning

confidence: 99%

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Donadio¹,

Maffioli²,

Monciardini³

et al. 2010

J Antibiot

224

126

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“…Many different posttranslational modifications are introduced into ribosomally synthesized peptides (4), and they often are required for biological activity, contributing structural properties and peptide stability (5). Because of the ribosomal origin of the peptides, variant generation can be accomplished readily by mutagenesis of the corresponding structural gene (6) or by the introduction of tailoring enzymes.…”

mentioning

confidence: 99%

Genome mining and genetic analysis of cypemycin biosynthesis reveal an unusual class of posttranslationally modified peptides

Claesen

Bibb

2010

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

133

203

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Posttranslational modification of amino acids confers a range of structural features and activities on ribosomally synthesized peptides, many of which have potent antimicrobial or other biological activities. Cypemycin is an extensively modified linear peptide produced by Streptomyces sp. OH-4156 with potent in vitro activity against mouse leukemia cells. Cypemycin does not contain lanthionine bridges but exhibits some of the structural features of lantibiotics, notably dehydrated threonines (dehydrobutyrines) and a C-terminal S-[(Z)-2-aminovinyl]-D-cysteine. Consequently it was classified as a member of the lantibiotic family of posttranslationally modified peptides. Cypemycin also possesses two L-allo-isoleucine residues and an N-terminal N,N-dimethylalanine, both unique amino acid modifications. We identified and heterologously expressed the cypemycin biosynthetic gene cluster and performed a mutational analysis of each individual gene. We show that even the previously described modifications are carried out by unusual enzymes or via a modification pathway unrelated to lantibiotic biosynthesis. Bioinformatic analysis revealed the widespread occurrence of cypemycinlike gene clusters within the bacterial kingdom and in the Archaea. Cypemycin is the founding member of an unusual class of posttranslationally modified ribosomally synthesized peptides, the linaridins.Actinomycetes | antibiotic | enzymology | natural products | Streptomyces

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“…The plasmid pAGvarX used in the construction of the plasmid pAGvar6 has been described previously. 12 The strain used to evaluate in vitro antimicrobial activity was Micrococcus luteus ATCC4698.…”

Section: Strains and Plasmidsmentioning

confidence: 99%

Organization of the biosynthetic genes encoding deoxyactagardine B (DAB), a new lantibiotic produced by Actinoplanes liguriae NCIMB41362

et al. 2010

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Deoxyactagardine B (DAB) is a hitherto unknown type B lantibiotic, produced by Actinoplanes liguriae NCIMB41362. The mature peptide is 19 amino acids in length and structurally analogous to actagardine, differing by two amino acids (V15L and I16V) and the absence of a sulfoxide bond between residues 14 and 19. The biosynthetic genes encoding DAB are clustered, and in addition to the structural gene ligA include genes believed to encode for the proteins responsible for the modification, transport and regulation of DAB synthesis. Surprisingly, despite the presence of a gene that shares significant homology to the monooxygenase garO from the actagardine biosynthetic gene cluster, the oxidized form of DAB has not been detected. A lanA gene encoding the DAB peptide has been introduced into the plasmid pAGvarX and delivered into a strain of Actinoplanes garbadinensis lacking the structural gene for actagardine, garA (A. garbadinensis DgarA). Expression of this gene in A. garbadinensis DgarA resulted in the production of actagardine B, an oxidized form of DAB.

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Organization of the genes encoding the biosynthesis of actagardine and engineering of a variant generation system

Cited by 61 publications

References 36 publications

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Genome mining and genetic analysis of cypemycin biosynthesis reveal an unusual class of posttranslationally modified peptides

Organization of the biosynthetic genes encoding deoxyactagardine B (DAB), a new lantibiotic produced by Actinoplanes liguriae NCIMB41362

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