Abstract
The Uridyl-Peptide Antibiotics (UPAs) are a diverse group of bacterial metabolites that are characterized by a uridyl moiety linked to a peptidic residue. Included in this group are the pacidamycins, liposidomycins, capuramycins, and muraymycins. Most of these antibiotics are produced by Streptomyces species and are naturally found as complexes of closely related congeners. The compounds all bear some resemblance to intermediates involved in cell wall biosynthesis in bacteria and exert their antibacterial action through inhibition of the membrane-bound translocase I. Caprazamycin was the first of the UPAs for which a biosynthetic gene cluster was identified and cloned, which quickly led to the discovery of several others. Preliminary experiments have been reported in which biosynthetic insights were applied to the production of analogs for evaluation of antimicrobial activity. Synthetic chemistry has provided evidence for the core features necessary for target inhibition and antibacterial efficacy. Although many of the UPAs have shown potent antibacterial activity, and are effective in inhibiting a highly selective bacterial target, none have progressed to become commercially viable agents. In this chapter, we will explore recent findings that have clarified the promise and limitations of this class of antibiotics.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Anderson MS, Eveland SS, Price NP (2000) Conserved cytoplasmic motifs that distinguish sub-groups of the polyprenol phosphate:N-acetylhexosamine-1-phosphate transferase family. FEMS Microb Lett 191:169–175
Bogatcheva E, Dubuisson T, Protopopova M, Einck L, Nacy CA, Reddy VM (2011) Chemical modification of capuramycins to enhance antibacterial activity. J Antimicrob Chemother 66:578–587
Bouhss A, Trunkfield AE, Bugg TD, Mengin-Lecreulx D (2008) The biosynthesis of peptidoglycan lipid-linked intermediates. FEMS Microbiol Rev 32:208–233
Brandish PE, Kimura KI, Inukai M, Southgate R, Lonsdale JT, Bugg TD (1996) Modes of action of tunicamycin, liposidomycin B, and mureidomycin A: inhibition of phospho-N-acetylmuramyl-pentapeptide translocase from Escherichia coli. Antimicrob Agents Chemother 40:1640–1644
Bugg TD, Braddick D, Dowson CG, Roper DI (2011) Bacterial cell wall assembly: still an attractive antibacterial target. Trends Biotechnol 29:167–173
Chatterjee S, Nadkarni SR, Vijayakumar EK, Patel MV, Ganguli BN, Fehlhaber HW, Vertesy L (1994) Napsamycins, new Pseudomonas active antibiotics of the mureidomycin family from Streptomyces sp. HIL Y-82,11372. J Antibiot (Tokyo) 47:595–598
Chen RH, Buko AM, Whittern DN, McAlpine JB (1989) Pacidamycins, a novel series of antibiotics with anti-Pseudomonas aeruginosa activity. II. Isolation and structural elucidation. J Antibiot 42:512–520
Deb Roy A, Gruschow S, Cairns N, Goss RJ (2010) Gene expression enabling synthetic diversification of natural products: chemogenetic generation of pacidamycin analogs. J Am Chem Soc 132:12243–12245
Dini C, Collette P, Drochon N, Guillot JC, Lemoine G, Mauvais P, Aszodi J (2000) Synthesis of the nucleoside moiety of liposidomycins: elucidation of the pharmacophore of this family of MraY inhibitors. Bioorg Med Chem Lett 10:1839–1843
Dini C, Didier-Laurent S, Drochon N, Feteanu S, Guillot JC, Monti F, Uridat E, Zhang J, Aszodi J (2002) Synthesis of sub-micromolar inhibitors of MraY by exploring the region originally occupied by the diazepanone ring in the liposidomycin structure. Bioorg Med Chem Lett 12:1209–1213
Dubuisson T, Bogatcheva E, Krishnan MY, Collins MT, Einck L, Nacy CA, Reddy VM (2010) In vitro antimicrobial activities of capuramycin analogues against non-tuberculous mycobacteria. J Antimicrob Chemother 65:2590–2597
Fujita Y, Kizuka M, Funabashi M, Ogawa Y, Ishikawa T, Nonaka K, Takatsu T (2011) A-90289 A and B, new inhibitors of bacterial translocase I, produced by Streptomyces sp. SANK 60405. J Antibiot 64:495–501
Fujita Y, Murakami R, Muramatsu Y, Miyakoshi S, Takatsu T (2008) A-94964, novel inhibitor of bacterial translocase I, produced by Streptomyces sp. SANK 60404. II. Physico-chemical properties and structure elucidation. J Antibiot 61:545–549
Gruschow S, Rackham EJ, Elkins B, Newill PL, Hill LM, Goss RJ (2009) New pacidamycin antibiotics through precursor-directed biosynthesis. ChemBioChem 10:355–360
Grüschow S, Rackham EJ, Goss RJM (2011) Diversity in natural product families is governed by more than enzyme promiscuity alone: establishing control of the pacidamycin portfolio. Chem Sci 2:2182–2186
Hotoda H, Daigo M, Furukawa M, Murayama K, Hasegawa CA, Kaneko M, Muramatsu Y, Ishii MM, Miyakoshi S, Takatsu T, Inukai M, Kakuta M, Abe T, Fukuoka T, Utsui Y, Ohya S (2003a) Synthesis and antimycobacterial activity of capuramycin analogs. Part 2: acylated derivatives of capuramycin-related compounds. Bioor Med Chem Lett 13:2833–2836
Hotoda H, Furukawa M, Daigo M, Murayama K, Kaneko M, Muramatsu Y, Ishii MM, Miyakoshi S, Takatsu T, Inukai M, Kakuta M, Abe T, Harasaki T, Fukuoka T, Utsui Y, Ohya S (2003b) Synthesis and antimycobacterial activity of capuramycin analogs. Part 1: substitution of the azepan-2-one moiety of capuramycin. Bioor Med Chem Lett 13:2829–2832
Ii K, Ichikawa S, Al-Dabbagh B, Bouhss A, Matsuda A (2010) Function-oriented synthesis of simplified saprazamycins: discovery of oxazolidine-containing uridine derivatives as antibacterial agents against drug-resistant bacteria. J Med Chem 53:3793–3813
Inukai M, Isono F, Takahashi S, Enokita R, Sakaida Y, Haneishi T (1989) Mureidomycins A-D, novel peptidylnucleoside antibiotics with spheroplast forming activity. I. Taxonomy, fermentation, isolation and physico-chemical properties. J Antibiot 42:662–666
Inukai M, Isono F, Takatsuki A (1993) Selective inhibition of the bacterial translocase reaction in peptidoglycan synthesis by mureidomycins. Antimicrob Agents Chemother 37:980–983
Isono F, Inukai M (1991) Mureidomycin A, a new inhibitor of bacterial peptidoglycan synthesis. Antimicrob Agents Chemother 35:234–236
Isono K, Uramoto M, Kusakabe H, Kimura K, Isaki K, Nelson CC, McCloskey JA (1985) Liposidomycins: novel nucleoside antibiotics which inhibit bacterial peptidoglycan synthesis. J Antibiot 38:1617–1621
Kaysser L, Eitel K, Tanino T, Siebenberg S, Matsuda A, Ichikawa S, Gust B (2010a) A new arylsulfate sulfotransferase involved in liponucleoside antibiotic biosynthesis in streptomycetes. J Biol Chem 285:12684–12694
Kaysser L, Lutsch L, Siebenberg S, Wemakor E, Kammerer B, Gust B (2009) Identification and manipulation of the caprazamycin gene cluster lead to new simplified liponucleoside antibiotics and give insights into the biosynthetic pathway. J Biol Chem 284:14987–14996
Kaysser L, Tang X, Wemakor E, Sedding K, Hennig S, Siebenberg S, Gust B (2011) Identification of a napsamycin biosynthesis gene cluster by genome mining. ChemBioChem 12:477–487
Kaysser L, Wemakor E, Siebenberg S, Salas JA, Sohng JK, Kammerer B, Gust B (2010b) Formation and attachment of the deoxysugar moiety and assembly of the gene cluster for caprazamycin biosynthesis. Appl Environ Microbiol 76:4008–4018
Koga T, Fukuoka T, Doi N, Harasaki T, Inoue H, Hotoda H, Kakuta M, Muramatsu Y, Yamamura N, Hoshi M, Hirota T (2004) Activity of capuramycin analogues against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare in vitro and in vivo. J Antimicrob Chemother 54:755–760
Le Corre L, Gravier-Pelletier C, Le Merrer Y (2007) Towards new MraY inhibitors: a serine template for uracil and 5-amino-5-deoxyribosyl scaffolding. Eur J Org Chemistry 32:5386–5394
Li Y-B, Xie Y-Y, Du N-N, Lu Y, Xu H-Z, Wang B, Yu Y, Liu Y-X, Song D-Q, Chen R-X (2011) Synthesis and in vitro antitubercular evaluation of novel sansanmycin derivatives. Bioorg Med Chem Lett 21:6804–6807
Lin YI, Li Z, Francisco GD, McDonald LA, Davis RA, Singh G, Yang Y, Mansour TS (2002) Muraymycins, novel peptidoglycan biosynthesis inhibitors: semisynthesis and SAR of their derivatives. Bioorg Med Chem Lett 12:2341–2344
McDonald LA, Barbieri LR, Carter GT, Kruppa G, Feng X, Lotvin JA, Siegel MM (2003) FTMS structure elucidation of natural products: application to muraymycin antibiotics using ESI multi-CHEF SORI-CID FTMS(n), the top-down/bottom-up approach, and HPLC ESI capillary-skimmer CID FTMS. Anal Chem 75:2730–2739
McDonald LA, Barbieri LR, Carter GT, Lenoy E, Lotvin J, Petersen PJ, Siegel MM, Singh G, Williamson RT (2002) Structures of the muraymycins, novel peptidoglycan biosynthesis inhibitors. J Am Chem Soc 124:10260–10261
Murakami R, Fujita Y, Kizuka M, Kagawa T, Muramatsu Y, Miyakoshi S, Takatsu T, Inukai M (2007) A-102395, a new inhibitor of bacterial translocase I, produced by Amycolatopsis sp. SANK 60206. J Antibiot (Tokyo) 60:690–695
Murakami R, Fujita Y, Kizuka M, Kagawa T, Muramatsu Y, Miyakoshi S, Takatsu T, Inukai M (2008) A-94964, a novel inhibitor of bacterial translocase I, produced by Streptomyces sp. SANK 60404. I. Taxonomy, isolation and biological activity. J Antibiot (Tokyo) 61:537–544
Nikonenko BV, Reddy VM, Protopopova M, Bogatcheva E, Einck L, Nacy CA (2009) Activity of SQ641, a capuramycin analog, in a murine model of tuberculosis. Antimicrob Agents Chemother 53:3138–3139
Price NP, Momany FA (2005) Modeling bacterial UDP-HexNAc: polyprenol-P HexNAc 1-P transferases. Glycobiology 15:29R–42R
Rackham EJ, Gruschow S, Ragab AE, Dickens S, Goss RJ (2010) Pacidamycin biosynthesis: identification and heterologous expression of the first uridyl peptide antibiotic gene cluster. ChemBioChem 11:1700–1709
Reddy VM, Einck L, Nacy CA (2008) In vitro antimycobacterial activities of capuramycin analogues. Antimicrob Agents Chemother 52:719–721
Siebenberg S, Kaysser L, Wemakor E, Heide L, Gust B, Kammerer B (2011) Identification and structural elucidation of new caprazamycins from Streptomyces sp. MK730-62F2 by liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 25:495–502
Spork AP, Wiegmann D, Granitzka M, Stalke D, Ducho C (2011) Stereoselective synthesis of uridine-derived nucleosyl amino acids. J Org Chem 76:10083–10098
Stachyra T, Dini C, Ferrari P, Bouhss A, van Heijenoort J, Mengin-Lecreulx D, Blanot D, Biton J, Le Beller D (2004) Fluorescence detection-based functional assay for high-throughput screening for MraY. Antimicrob Agents Chemother 48:897–902
Tanino T, Al-Dabbagh B, Mengin-Lecreulx D, Bouhss A, Oyama H, Ichikawa S, Matsuda A (2011) Mechanistic analysis of muraymycin analogues: a guide to the design of MraY inhibitors. J Med Chem 54:8421–8439
Tanino T, Ichikawa S, Al-Dabbagh B, Bouhss A, Oyama H, Matsuda A (2010a) Synthesis and biological evaluation of muraymycin analogues active against anti-drug resistant bacteria. ACS Med Chem Lett 1:258–262
Tanino T, Ichikawa S, Shiro M, Matsuda A (2010b) Total synthesis of (-)-muraymycin D2 and its epimer. J Org Chem 75:1366–1377
Walsh CT, Zhang W (2011) Chemical logic and enzymatic machinery for biological assembly of peptidyl nucleoside antibiotics. ACS Chem Biol 6:1000–1007
Winn M, Goss RJ, Kimura K, Bugg TD (2010) Antimicrobial nucleoside antibiotics targeting cell wall assembly: recent advances in structure-function studies and nucleoside biosynthesis. Nat Prod Rep 27:279–304
Xie Y, Chen R, Si S, Sun C, Xu H (2007) A new nucleosidyl-peptide antibiotic, sansanmycin. J Antibiot 60:158–161
Yamaguchi H, Sato S, Yoshida S, Takada K, Itoh M, Seto H, Otake N (1986) Capuramycin, a new nucleoside antibiotic. Taxonomy, fermentation, isolation and characterization. J Antibiot (Tokyo) 39:1047–1053
Yamashita A, Norton E, Petersen PJ, Rasmussen BA, Singh G, Yang Y, Mansour TS, Ho DM (2003) Muraymycins, novel peptidoglycan biosynthesis inhibitors: synthesis and SAR of their analogues. Bioorg Med Chem Lett 13:3345–3350
Zhang W, Ntai I, Bolla ML, Malcolmson SJ, Kahne D, Kelleher NL, Walsh CT (2011a) Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics. J Am Chem Soc 133:5240–5243
Zhang W, Ntai I, Neil LK, Christopher TW (2011b) tRNA-dependent peptide bond formation by the transferase PacB in biosynthesis of the pacidamycin group of pentapeptidyl nucleoside antibiotics. PNAS 108:12249–12253
Zhang W, Ostash B, Christopher TW (2010) Identification of the biosynthetic gene cluster for the pacidamycin group of peptidyl nucleoside antibiotics. PNAS 107:16828–16833
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Carter, G.T., McDonald, L.A. (2014). Uridyl Peptide Antibiotics: Developments in Biosynthesis and Medicinal Chemistry. In: Marinelli, F., Genilloud, O. (eds) Antimicrobials. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-39968-8_9
Download citation
DOI: https://doi.org/10.1007/978-3-642-39968-8_9
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-39967-1
Online ISBN: 978-3-642-39968-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)