Mining of the Pyrrolamide Antibiotics Analogs in Streptomyces netropsis Reveals the Amidohydrolase-Dependent “Iterative Strategy” Underlying the Pyrrole Polymerization
In biosynthesis of natural products, potential intermediates or analogs of a particular compound in the crude extracts are commonly overlooked in routine assays due to their low concentration, limited structural information, or because of their insignificant bio-activities. This may lead into an incomplete and even an incorrect biosynthetic pathway for the target molecule. Here we applied multiple compound mining approaches, including genome scanning and precursor ion scan-directed mass spectrometry, to identify potential pyrrolamide compounds in the fermentation culture of Streptomyces netropsis. Several novel congocidine and distamycin analogs were thus detected and characterized. A more reasonable route for the biosynthesis of pyrrolamides was proposed based on the structures of these newly discovered compounds, as well as the functional characterization of several key biosynthetic genes of pyrrolamides. Collectively, our results implied an unusual “iterative strategy” underlying the pyrrole polymerization in the biosynthesis of pyrrolamide antibiotics.
References
[1]
Cragg GM, Newman DJ (2013) Natural products: A continuing source of novel drug leads. Biochimica et Biophysica Acta 1830: 3670–3695. doi: 10.1016/j.bbagen.2013.02.008
[2]
Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. Journal of Natural Products 75: 311–335. doi: 10.1021/np200906s
[3]
Baker DD, Chu M, Oza U, Rajgarhia V (2007) The value of natural products to future pharmaceutical discovery. Natural Product Reports 24: 1225–1244. doi: 10.1039/b602241n
[4]
Nett M, Ikeda H, Moore BS (2009) Genomic basis for natural product biosynthetic diversity in the actinomycetes. Natural Product Reports 26: 1362–1384. doi: 10.1039/b817069j
[5]
Qu XD, Lei C, Liu W (2011) Transcriptome mining of active biosynthetic pathways and their associated products in Streptomyces flaveolus. Angewandte Chemie-International Edition 50: 9651–9654. doi: 10.1002/anie.201103085
[6]
Kersten RD, Yang YL, Xu YQ, Cimermancic P, Nam SJ, et al. (2011) A mass spectrometry-guided genome mining approach for natural product peptidogenomics. Nature Chemical Biology 7: 794–802. doi: 10.1038/nchembio.684
[7]
Bumpus SB, Evans BS, Thomas PM, Ntai I, Kelleher NL (2009) A proteomics approach to discovering natural products and their biosynthetic pathways. Nature Biotechnology 27: 951–U120. doi: 10.1038/nbt.1565
[8]
Wilkinson B, Micklefield J (2007) Mining and engineering natural-product biosynthetic pathways. Nature Chemical Biology 3: 379–386. doi: 10.1038/nchembio.2007.7
[9]
Menzella HG, Reeves CD (2007) Combinatorial biosynthesis for drug development. Current Opinion in Microbiology 10: 238–245. doi: 10.1016/j.mib.2007.05.005
[10]
Challis GL (2008) Mining microbial genomes for new natural products and biosynthetic pathways. Microbiology-Sgm 154: 1555–1569. doi: 10.1099/mic.0.2008/018523-0
[11]
Cane DE, Ikeda H (2012) Exploration and Mining of the Bacterial Terpenome. Accounts of Chemical Research 45: 463–472. doi: 10.1021/ar200198d
Hertweck C (2009) Hidden biosynthetic treasures brought to light. Nature Chemical Biology 5: 450–452. doi: 10.1038/nchembio0709-450
[14]
Nguyen DD, Wu CH, Moree WJ, Lamsa A, Medema MH, et al. (2013) MS/MS networking guided analysis of molecule and gene cluster families. Proceedings of the National Academy of Sciences of the United States of America 110: E2611–2620. doi: 10.1073/pnas.1303471110
[15]
Neidle S (2001) DNA minor-groove recognition by small molecules. Natural Product Reports 18: 291–309. doi: 10.1039/a705982e
[16]
Asai A, Sakai Y, Ogawa H, Yamashita Y, Kakita S, et al. (2000) Pyrronamycin A and B, novel antitumor antibiotics containing pyrrole-amide repeating unit, produced by Streptomyces sp. Journal of Antibiotics 53: 66–69. doi: 10.7164/antibiotics.53.66
[17]
Barrett MP, Gemmell CG, Suckling CJ (2013) Minor groove binders as anti-infective agents. Pharmacology & therapeutics 139: 12–23. doi: 10.1016/j.pharmthera.2013.03.002
[18]
Matteoli B, Bernardini S, Iuliano R, Parenti S, Freer G, et al. (2008) In vitro antiviral activity of distamycin A against clinical isolates of herpes simplex virus 1 and 2 from transplanted patients. Intervirology 51: 166–172. doi: 10.1159/000148199
[19]
Sharma S, Doherty KM, Brosh RM Jr (2005) DNA helicases as targets for anti-cancer drugs. Current Medicinal Chemistry Anti-Cancer Agents 5: 183–199. doi: 10.2174/1568011053765985
[20]
Fuchs JE, Spitzer GM, Javed A, Biela A, Kreutz C, et al. (2011) Minor groove binders and drugs targeting proteins cover complementary regions in chemical shape space. Journal of Chemical Information and Modeling 51: 2223–2232. doi: 10.1021/ci200237c
[21]
Baraldi PG, Nunez MD, Espinosa A, Romagnoli R (2004) Distamycin A as stem of DNA minor groove alkylating agents. Current Topics in Medicinal Chemistry 4: 231–239. doi: 10.2174/1568026043451474
[22]
Uria-Nickelsen M, Blodgett A, Kamp H, Eakin A, Sherer B, et al. (2013) Novel DNA gyrase inhibitors: Microbiological characterisation of pyrrolamides. International Journal of Antimicrobial Agents 41: 28–35. doi: 10.1016/j.ijantimicag.2012.08.017
[23]
Iyer P, Srinivasan A, Singh SK, Mascara GP, Zayitova S, et al. (2013) Synthesis and characterization of DNA minor groove binding alkylating agents. Chemical Research in Toxicology 26: 156–168. doi: 10.1021/tx300437x
[24]
Juguet M, Lautru S, Francou FX, Nezbedova S, Leblond P, et al. (2009) An iterative nonribosomal peptide synthetase assembles the pyrrole-amide antibiotic congocidine in Streptomyces ambofaciens. Chemistry & Biology 16: 421–431. doi: 10.1016/j.chembiol.2009.03.010
[25]
Lautru S, Song LJ, Demange L, Lombes T, Galons H, et al. (2012) A Sweet origin for the key congocidine precursor 4-acetamidopyrrole-2-carboxylate. Angewandte Chemie-International Edition 51: 7454–7458. doi: 10.1002/anie.201201445
[26]
Cordell GA, Shin YG (1999) Finding the needle in the haystack. The dereplication of natural product extracts. Pure and Applied Chemistry 71: 1089–1094. doi: 10.1351/pac199971061089
[27]
Lang G, Mayhudin NA, Mitova MI, Sun L, van der Sar S, et al. (2008) Evolving trends in the dereplication of natural product extracts: New methodology for rapid, small-scale investigation of natural product extracts. Journal of Natural Products 71: 1595–1599. doi: 10.1021/np8002222
[28]
Bode HB, Bethe B, Hofs R, Zeeck A (2002) Big effects from small changes: possible ways to explore nature's chemical diversity. ChemBioChem 3: 619–627. doi: 10.1002/1439-7633(20020703)3:7<619::aid-cbic619>3.0.co;2-9
[29]
Hur GH, Vickery CR, Burkart MD (2012) Explorations of catalytic domains in non-ribosomal peptide synthetase enzymology. Natural Prodduct Reports 29: 1074–1098. doi: 10.1039/c2np20025b
[30]
Yamanaka K, Maruyama C, Takagi H, Hamano Y (2008) Epsilon-poly-L-lysine dispersity is controlled by a highly unusual nonribosomal peptide synthetase. Nature Chemical Biology 4: 766–772. doi: 10.1038/nchembio.125
[31]
Yamanaka K, Kito N, Imokawa Y, Maruyama C, Utagawa T, et al. (2010) Mechanism of epsilon-poly-L-lysine production and accumulation revealed by identification and analysis of an epsilon-poly-L-lysine-degrading enzyme. Appllied and Environmental Microbiology 76: 5669–5675. doi: 10.1128/aem.00853-10
[32]
Rose TM, Henikoff JG, Henikoff S (2003) CODEHOP (COnsensus-DEgenerate hybrid oligonucleotide primer) PCR primer design. Nucleic Acids Research 31: 3763–3766. doi: 10.1093/nar/gkg524
[33]
Yu Y, Duan L, Zhang Q, Liao R, Ding Y, et al. (2009) Nosiheptide biosynthesis featuring a unique indole side ring formation on the characteristic thiopeptide framework. ACS Chemical Biology 4: 855–864. doi: 10.1021/cb900133x
