Studies on the biosynthesis of the lipodepsipeptide antibiotic Ramoplanin A2

Hoertz, Amanda J.; Hamburger, James B.; Gooden, David M.; Bednar, Maria M.; McCafferty, Dewey G.

doi:10.1016/j.bmc.2011.11.062

Cited by 17 publications

(10 citation statements)

References 37 publications

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“…Examples of such exceptions include starter modules, which contain an adenylation domain but lack a condensation domain, and initiate biosynthesis ( 59 , 60 ). Modules which lack a catalytic condensation domain may also be activated in trans by a module on another open reading frame lacking an adenylation domain ( 45 , 61 , 62 ). Still other extra-modular adenylation domains are been implicated in nonproteinogenic amino acid biosynthesis ( 63 – 65 ) or starter unit ( 66 , 67 ) activation.…”

Section: Methodsmentioning

confidence: 99%

Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM)

et al. 2015

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Microbial natural products are an invaluable source of evolved bioactive small molecules and pharmaceutical agents. Next-generation and metagenomic sequencing indicates untapped genomic potential, yet high rediscovery rates of known metabolites increasingly frustrate conventional natural product screening programs. New methods to connect biosynthetic gene clusters to novel chemical scaffolds are therefore critical to enable the targeted discovery of genetically encoded natural products. Here, we present PRISM, a computational resource for the identification of biosynthetic gene clusters, prediction of genetically encoded nonribosomal peptides and type I and II polyketides, and bio- and cheminformatic dereplication of known natural products. PRISM implements novel algorithms which render it uniquely capable of predicting type II polyketides, deoxygenated sugars, and starter units, making it a comprehensive genome-guided chemical structure prediction engine. A library of 57 tailoring reactions is leveraged for combinatorial scaffold library generation when multiple potential substrates are consistent with biosynthetic logic. We compare the accuracy of PRISM to existing genomic analysis platforms. PRISM is an open-source, user-friendly web application available at http://magarveylab.ca/prism/.

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Section: Methodsmentioning

confidence: 99%

Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM)

et al. 2015

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“…ATCC33076 in 2002 [ 10 ]. The analysis showed that the consecutive action of four NRPSs ( ram12 , 13 , 14 and 17 ) assembled the peptide core of ramoplanin containing a mixture of L and D amino acids (nine L, seven D) as well as several nonproteinogenic side chains [ 11 ]. To investigate the glycosylation mechanism in ramoplanin biosynthesis ram29 was inactivated and mutant strain A .…”

Section: Introductionmentioning

confidence: 99%

Production of the Ramoplanin Activity Analogue by Double Gene Inactivation

et al. 2016

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Glycopeptides such as vancomycin and telavancin are essential for treating infections caused by Gram-positive bacteria. But the dwindling availability of new antibiotics and the emergence of resistant bacteria are making effective antibiotic treatment increasingly difficult. Ramoplanin, an inhibitor of bacterial cell wall biosynthesis, is a highly effective antibiotic against a wide range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate resistant Clostridium difficile and vancomycin-resistant Enterococcus sp. Here, two tailoring enzyme genes in the biosynthesis of ramoplanin were deleted by double in-frame gene knockouts to produce new ramoplanin derivatives. The deschlororamoplanin A2 aglycone was purified and its structure was identified with LC-MS/MS. Deschlororamoplanin A2 aglycone and ramoplanin aglycone showed similar activity to ramoplanin A2. The results showed that α-1,2-dimannosyl disaccharide at Hpg11 and chlorination at Chp17 in the ramoplanin structure are not essential for its antimicrobial activity. This work provides new precursor compounds for the semisynthetic modification of ramoplanin.

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“…The fatty acid side chain lengths and/or degrees of saturation are the only differences between the rotihibin C and D analogues. The desaturation could be explained by the presence of two acyl-CoA dehydrogenases (RthI and RthJ), similar to the situation in the ramoplanin biosynthetic gene cluster ( 48 ). One is expected to introduce the first double bond, while the second additional dehydrogenation is possibly not essential.…”

Section: Resultsmentioning

confidence: 68%