Genomic scanning enabling discovery of a new antibacterial bicyclic carbamate-containing alkaloid  

作　　者：Qing Fang Linrui Wu Caroline Urwald Morgane Mugat Shan Wang Kwaku Kyeremeh Carol Philips Samantha Law d Yongjun Zhou Hai Deng 

机构地区：[1]Marine Biodiscovery Centre,Department of Chemistry,University of Aberdeen,Meston Walk,Aberdeen,AB243UE,Scotland,UK [2]ENSAIA,2 avenue de la forêt de Haye,54505 vandoeuvre lès Nancy,France [3]Department of Chemistry,University of Ghana,P.O.Box LG56,Legon-Accra,Ghana [4]NCIMB Ltd,Ferguson Building,Craibstone Estate,Bucksburn,Aberdeen,AB219YA,Scotland,UK [5]Research Centre for Marine Drugs,State Key Laboratory of Oncogenes and Related Genes,Department of Pharmacy,Ren Ji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,200127,China

出　　处：《Synthetic and Systems Biotechnology》2021年第1期12-19,共8页合成和系统生物技术（英文）

基　　金：QF and HD are grateful to the University of Aberdeen Elphinstone Scholarship and Scottish Funding Council/ScotCHEM for financial support through the PEER/PERCE Funding.HD and SW thank the financial supports of Biotechnology and Biological Sciences Research Council UK(BBSRC,BB/P00380X/1);HD,SAM and CP thank Business Interaction Vouchers(BIV009)from BBSRC funded Natural Products discovery and bioengineering Network(NPRONET);H.D.and K.K.thank the financial supports of Leverhulme Trust-Royal Society Africa award(AA090088);the jointly funded UK Medical Research Council-UK Department for International Development(MRC/DFID)Concordat agreement African Research Leaders Award(MR/S00520X/1);YZ and HD thank National Natural Science Foundation of China(31929001).

摘　　要：Non-ribosomal peptides are a group of structurally diverse natural products with various important therapeutic and agrochemical applications.Bacterial pyrrolizidine alkaloids(PAs),containing a scaffold of two fused five-membered ring system with a nitrogen atom at the bridgehead,have been found to originate from a multidomain non-ribosomal peptide synthetase to generate indolizidine intermediates,followed by multistep oxidation,catalysed by single Bayer-Villiger(BV)enzymes,to yield PA scaffolds.Although bacterial PAs are rare in natural product inventory,bioinformatics analysis suggested that the biosynthetic gene clusters(BGCs)that are likely to be responsible for the production of PA-like metabolites are widely distributed in bacterial genomes.However,most of the strains containing PA-like BGCs are not deposited in the public domain,therefore preventing further assessment of the chemical spaces of this group of bioactive metabolites.Here,we report a genomic scanning strategy to assess the potential of PA metabolites production in our culture collection without prior knowledge of genome information.Among the strains tested,we found fifteen contain the key BV enzymes that are likely to be involved in the last step of PA ring formation.Subsequently one-strain-many-compound(OSMAC)method,supported by a combination of HR-MS,NMR,SMART 2.0 technology,and GNPS analysis,allowed identification and characterization of a new[5+7]heterobicyclic carbamate,legoncarbamate,together with five known PAs,bohemamine derivatives,from Streptomyces sp.CT37,a Ghanaian soil isolate.The absolute stereochemistry of legoncarbamate was determined by comparison of measured and calculated ECD spectra.Legoncarbamate displays antibacterial activity against E.coli ATCC 25922 with an MIC value of 3.1μg/mL.Finally,a biosynthetic model of legoncarbamate and other bohemamines was proposed based on the knowledge we have gained so far.

关 键 词：Genomic scanning Bayer villiger monooxygenase Carbamate alkaloids Pyrrolizidine alkaloids Non-ribosomal peptide synthetases 

分 类 号：O62[理学—有机化学]