Review – Lichen-Associated Bacteria as a Hot Spot of Chemodiversity: Focus on Uncialamycin, a Promising Compound for Future Medicinal Applications

Abstract

This review presents the state of knowledge on the medicinal potential of bacteria associated with lichens. In fact, besides the classical symbiotic partners (photobiont and mycobiont) forming the lichen thallus, associated bacteria have been recently described as a third partner. Various studies demonstrated the diversity of these communities with a predominance of Alphaproteobacteria. Bacterial groups more relevant for secondary metabolite synthesis have also been revealed. This article summarizes studies reporting the abilities of these communities to produce metabolites with relevant bioactivities. The biotechnological interest of these bacteria for drug discovery is highlighted regarding the production of compounds with therapeutic potential. Special focus is given to the synthesis of the most promising compound, uncialamycin, a potent enediyne isolated from a Streptomyces sp. associated with Cladonia uncialis.

Key words

lichens - bacterial communities - chemodiversity - drug discovery - bioactive compounds - uncialamycin

^* These authors contributed equally to this paper.

• References

• 1 Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K. A new antibiotic kills pathogens without detectable resistance. Nature 2015; 517: 455-459
• 2 Lauterwein M, Oethinger M, Belsner K, Peters T, Marre R. In vitro activities of the lichen secondary metabolites vulpinic acid, (+)-usnic acid, and (−)-usnic acid against aerobic and anaerobic microorganisms. Antimicrob Agents Chemother 1995; 39: 2541-2543
• 3 Ingólfsdóttir K. Usnic acid. Phytochemistry 2002; 61: 729-736
• 4 Molnár K, Farkas E. Current results on biological activities of lichen secondary metabolites: a review. Z Naturforsch C 2010; 65: 157-173
• 5 Shrestha G, St Clair LL. Lichens: a promising source of antibiotic and anticancer drugs. Phytochem Rev 2013; 12: 229-244
• 6 Shukla V, Joshi GP, Rawat MSM. Lichens as a potential natural source of bioactive compounds: a review. Phytochem Rev 2010; 9: 303-314
• 7 Boustie J, Grube M. Lichens – a promising source of bioactive secondary metabolites. Plant Genet Ressources 2005; 3: 273-287
• 8 Boustie J, Tomasi S, Grube M. Bioactive lichen metabolites: alpine habitats as an untapped source. Phytochem Rev 2011; 10: 287-307
• 9 Hawksworth DL. The lichenicolous fungi of Great Britain and Ireland: an overview and annotated checklist. Lichenologist 2003; 35: 191-232
• 10 Lawrey J, Diederich P. Lichenicolous fungi: interactions, evolution, and biodiversity. Bryologist 2003; 106: 80-120
• 11 González I, Ayuso-Sacido A, Anderson A, Genilloud O. Actinomycetes isolated from lichens: evaluation of their diversity and detection of biosynthetic gene sequences. FEMS Microbiol Ecol 2005; 54: 401-415
• 12 Cardinale M, Puglia AM, Grube M. Molecular analysis of lichen-associated bacterial communities. FEMS Microbiol Ecol 2006; 57: 484-495
• 13 Cardinale M, Vieira de Castro jr. J, Müller H, Berg G, Grube M. In situ analysis of the bacterial community associated with the reindeer lichen Cladonia arbuscula reveals predominance of Alphaproteobacteria. FEMS Microbiol Ecol 2008; 66: 63-71
• 14 Cardinale M, Grube M, Castro jr. JV, Müller H, Berg G. Bacterial taxa associated with the lung lichen Lobaria pulmonaria are differentially shaped by geography and habitat. FEMS Microbiol Lett 2012; 329: 111-115
• 15 Liba CM, Ferrara FIS, Manfio GP, Fantinatti-Garboggini F, Albuquerque RC, Pavan C, Ramos PL, Moreira-Filho C, Barbosa HR. Nitrogen-fixing chemo-organotrophic bacteria isolated from cyanobacteria-deprived lichens and their ability to solubilize phosphate and to release amino acids and phytohormones. J Appl Microbiol 2006; 101: 1076-1086
• 16 Grube M, Berg G. Microbial consortia of bacteria and fungi with focus on the lichen symbiosis. Fungal Biol Rev 2009; 23: 72-85
• 17 Grube M, Cardinale M, de Castro jr. JV, Müller H, Berg G. Species-specific structural and functional diversity of bacterial communities in lichen symbioses. ISME J 2009; 3: 1105-1115
• 18 Hodkinson BP, Lutzoni F. A microbiotic survey of lichen-associated bacteria reveals a new lineage from the Rhizobiales. Symbiosis 2009; 49: 163-180
• 19 Schneider T, Schmid E, de Castro jr. JV, Cardinale M, Eberl L, Grube M, Berg G, Riedel K. Structure and function of the symbiosis partners of the lung lichen (Lobaria pulmonaria L. Hoffm.) analyzed by metaproteomics. Proteomics 2011; 11: 2752-2756
• 20 Bates ST, Cropsey GWG, Caporaso JG, Knight R, Fierer N. Bacterial communities associated with the lichen symbiosis. Appl Environ Microbiol 2011; 77: 1309-1314
• 21 Muggia L, Vancurova L, Škaloud P, Peksa O, Wedin M, Grube M. The symbiotic playground of lichen thalli – a highly flexible photobiont association in rock-inhabiting lichens. FEMS Microbiol Ecol 2013; 85: 313-323
• 22 Grube M, Cernava T, Soh J, Fuchs S, Aschenbrenner I, Lassek C, Wegner U, Becher D, Riedel K, Sensen CW, Berg G. Exploring functional contexts of symbiotic sustain within lichen-associated bacteria by comparative omics. ISME J 2015; 9: 1-13
• 23 Cardinale M, Steinová J, Rabensteiner J, Berg G, Grube M. Age, sun and substrate: triggers of bacterial communities in lichens. Environ Microbiol Rep 2012; 4: 23-28
• 24 Grube M, Berg G, Andrésson ÓS, Vilhelmsson O, Dyer PS, Miao VPW. Lichen genomics: prospects and progress. In: Martin F, Editor The ecological genomics of fungi. New York: John Wiley & Sons; 2014: 191-212
• 25 Printzen C, Fernández-Mendoza F, Muggia L, Berg G, Grube M. Alphaproteobacterial communities in geographically distant populations of the lichen Cetraria aculeata . FEMS Microbiol Ecol 2012; 82: 316-325
• 26 Bjelland T, Grube M, Hoem S, Jorgensen SL, Daae FL, Thorseth IH, Øvreås L. Microbial metacommunities in the lichen-rock habitat. Environ Microbiol Rep 2011; 3: 434-442
• 27 An SY, Xiao T, Yokota A. Leifsonia lichenia sp. nov., isolated from lichen in Japan. J Gen Appl Microbiol 2009; 55: 339-343
• 28 An SY, Xiao T, Yokota A. Schumannella luteola gen. nov., sp. nov., a novel genus of the family Microbacteriaceae. J Gen Appl Microbiol 2008; 258: 253-258
• 29 Cheenpracha S, Vidor NB, Yoshida WY, Davies J, Chang LC. Coumabiocins A–F, aminocoumarins from an organic extract of Streptomyces sp. L-4-4. J Nat Prod 2010; 73: 880-884
• 30 Davies J, Wang H, Taylor T, Warabi K, Huang XH, Andersen RJ. Uncialamycin, a new enediyne antibiotic. Org Lett 2005; 7: 5233-5236
• 31 Li B, Xie CH, Yokota A. Nocardioides exalbidus sp. nov., a novel actinomycete isolated from lichen in Izu-Oshima Island, Japan. Actinomycetologica 2007; 21: 22-26
• 32 Motohashi K, Takagi M, Yamamura H, Hayakawa M, Shin-ya K. A new angucycline and a new butenolide isolated from lichen-derived Streptomyces spp. J Antibiot (Tokyo) 2010; 63: 545-548
• 33 Selbmann L, Zucconi L, Ruisi S, Grube M, Cardinale M, Onofri S. Culturable bacteria associated with Antarctic lichens: affiliation and psychrotolerance. Polar Biol 2009; 33: 71-83
• 34 Williams DE, Davies J, Patrick BO, Bottriell H, Tarling T, Roberge M, Andersen RJ. Cladoniamides A–G, tryptophan-derived alkaloids produced in culture by Streptomyces uncialis . Org Lett 2008; 10: 3501-3504
• 35 Parrot D, Antony-Babu S, Intertaglia L, Grube M, Tomasi S, Suzuki MT. Littoral lichens as a novel source of potentially bioactive Actinobacteria. Sci Rep 2015; 5: 15839
• 36 Yamamura H, Ashizawa H, Nakagawa Y, Hamada M, Ishida Y, Otoguro M, Tamura T, Hayakawa M. Actinomycetospora iriomotensis sp. nov., a novel actinomycete isolated from a lichen sample. J Antibiot 2011; 64: 289-292
• 37 Suzuki MT, Parrot D, Berg G, Grube M, Tomasi S. Lichens as natural sources of biotechnologically relevant bacteria. Appl Microbiol Biotechnol 2016; 100: 583-595
• 38 Grube M, Köberl M, Lackner S, Berg C, Berg G. Host-parasite interaction and microbiome response: effects of fungal infections on the bacterial community of the Alpine lichen Solorina crocea . FEMS Microbiol Ecol 2012; 82: 472-481
• 39 Hodkinson BP, Gottel NR, Schadt CW, Lutzoni F. Photoautotrophic symbiont and geography are major factors affecting highly structured and diverse bacterial communities in the lichen microbiome. Environ Microbiol 2012; 14: 147-161
• 40 Mushegian AA, Peterson CN, Baker CMC, Pringle A. Bacterial diversity across individual lichens. Appl Environ Microbiol 2011; 77: 4249-4252
• 41 Sigurbjörnsdóttir MA, Heiðmarsson S, Jónsdóttir AR, Vilhelmsson O. Novel bacteria associated with Arctic seashore lichens have potential roles in nutrient scavenging. Can J Microbiol 2014; 92: 307-317
• 42 Navarro-Noya YE, Jiménez-Aguilar A, Valenzuela-Encinas C, Alcántara-Hernández J, Ruíz-Valdiviezo VM, Ponce-Mendoza A, Luna-Guido M, Marsch R, Dendooven L. Bacterial communities in soil under moss and lichen-moss crusts. Geomicrobiol J 2014; 31: 152-160
• 43 Davies J, Ryan KS. Introducing the parvome: bioactive compounds in the microbial world. ACS Chem Biol 2012; 7: 252-259
• 44 Williams DE, Bottriell H, Davies J, Tietjen I, Brockman MA, Andersen RJ. Unciaphenol, an Oxygenated Analogue of the Bergman Cyclization Product of Uncialamycin Exhibits Anti-HIV Activity. Org Lett 2015; 17: 5304-5307
• 45 Cardinale M, Grube M, Berg G. Frondihabitans cladoniiphilus sp. nov., an actinobacterium of the family Microbacteriaceae isolated from lichen, and emended description of the genus Frondihabitans. Int J Syst Evol Microbiol 2011; 61: 3033-3038
• 46 Singh S, Garrity G, Genillourd O, Lingham R, Martin I, Nallin-Omstead M, Silverman K, Zink D. Inhibitor compounds of farnesyl-protein transferase and chemotherapeutic compositions containing the same, produced by strain ATCC 55532. US Patent 5627057, 1997
• 47 Braña AF, Fiedler HP, Nava H, González V, Sarmiento-Vizcaíno A, Molina A, Acuña JL, García LA, Blanco G. Two Streptomyces species producing antibiotic, antitumor, and anti-inflammatory compounds are widespread among intertidal macroalgae and deep-sea coral reef invertebrates from the central Cantabrian Sea. Microb Ecol 2015; 69: 512-524
• 48 Takahashi Y, Omura S. Isolation of new actinomycete strains for the screening of new bioactive compounds. J Gen Appl Microbiol 2003; 49: 141-154
• 49 Murphy B, Jensen P, Fenical W. The chemistry of marine bacteria. In: Fattorusso E, Gerwick W, Taglialatela-Scafati O, editors Handbook of marine natural products. Dordrecht: Springer Netherlands; 2012: 153-190
• 50 Waters B, Saxena G, Wanggui Y, Kau D, Wrigley S, Stokesd R, Davies J. Identifying protein kinase inhibitors using an assay based on inhibition of aerial hyphae formation in Streptomyces . J Antibiot 2002; 55: 407-416
• 51 Yao G, Vidor NB, Foss AP, Chang LC. Lemnalosides A–D, decalin-type bicyclic diterpene glycosides from the marine soft coral Lemnalia sp. J Nat Prod 2007; 70: 901-905
• 52 Raad I, Hachem R, Abi-Said D, Rolston K, Whimbey E, Buzaid A, Legha S. A prospective crossover randomized trial of novobiocin and rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2. Cancer 1998; 82: 403-411
• 53 Walsh TJ, Standiford HC, Reboli AC, John JF, Mulligan ME, Ribner BS, Montgomerie JZ, Goetz MB, Mayhall CG, Rimland D. Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome. Antimicrob Agents Chemother 1993; 37: 1334-1342
• 54 Konishi M, Ohkuma H, Tsuno T, Oki T. Crystal and molecular structure of dynemicin 1: a novel 1, 5-diyn-3-ene antitumor antibiotic. J Am Chem Soc 1990; 112: 3715-3716
• 55 Nicolaou KC, Chen JS, Zhang H, Montero A. Asymmetric synthesis and biological properties of uncialamycin and 26-epi-uncialamycin. Angew Chem Int Ed Engl 2008; 47: 185-189
• 56 Jean M, Tomasi S, van de Weghe P. When the nine-membered enediynes play hide and seek. Org Biomol Chem 2012; 10: 7453-7456
• 57 Damle NK. Tumour-targeted chemotherapy with immunoconjugates of calicheamicin. Expert Opin Biol Ther 2004; 4: 1445-1452
• 58 Berger M, Leopold L, Dowell J, Korth-Bradley J, Sherman M. Licensure of gemtuzumab ozogamicin for the treatment of selected patients 60 years of age or older with acute myeloid leukemia in first relapse. Invest New Drugs 2002; 20: 395-406
• 59 Hamann PR, Hinman LM, Beyer CF, Greenberger LM, Lin C, Lindh D, Menendez AT, Wallace R, Durr FE, Upeslacis J. An anti-MUC1 antibody-calicheamicin conjugate for treatment of solid tumors. Choice of linker and overcoming drug resistance. Bioconjug Chem 2005; 16: 346-353
• 60 Bergman RG. Reactive 1, 4-dehydroaromatics. Acc Chem Res 1973; 6: 25-31
• 61 Myers AG, Fraley ME, Tom NJ, Cohen SB, Madar DJ. Synthesis of (+)-dynemicin A and analogs of wide structural variability: establishment of the absolute configuration of natural dynemicin A. Chem Biol 1995; 2: 33-43
• 62 Smith AL, Nicolaou KC. The enediyne antibiotics. J Med Chem 1996; 39: 2103-2117
• 63 Sanchez C, Mendez C, Salas JA. Indolocarbazole natural products: occurrence, biosynthesis, and biological activity. Nat Prod Rep 2006; 23: 1007-1045
• 64 Howard-Jones AR, Walsh CT. Staurosporine and rebeccamycin aglycones are assembled by the oxidative action of StaP, StaC, and RebC on chromopyrrolic acid. J Am Chem Soc 2006; 128: 12289-12298
• 65 Hyun CG, Bililign T, Liao J, Thorson JS. The biosynthesis of indolocarbazoles in a heterologous E. coli host. Chembiochem 2003; 4: 114-117
• 66 Howard-Jones AR, Walsh CT. Enzymatic generation of the chromopyrrolic acid scaffold of rebeccamycin by the tandem action of RebO and RebD. Biochemistry 2005; 44: 15652-15663
• 67 Sánchez C, Méndez C, Salas J. Engineering biosynthetic pathways to generate antitumor indolocarbazole derivatives. J Ind Microbiol Biotechnol 2006; 33: 560-568
• 68 Sánchez C, Zhu L, Braña AF, Salas AP, Rohr J, Méndez C, Salas JA. Combinatorial biosynthesis of antitumor indolocarbazole compounds. Proc Natl Acad Sci U S A 2005; 102: 461-466
• 69 Zhang C, Albermann C, Fu X, Peters NR, Chisholm JD, Zhang G, Gilbert EJ, Wang PG, Van Vranken DL, Thorson JS. RebG- and RebM-catalyzed indolocarbazole diversification. Chembiochem 2006; 7: 795-804
• 70 Singh SB, Liesch JM, Lingham RB, Goetz MA, Gibbst JB. Actinoplanic acid A: a macrocyclic polycarboxylic acid which is a potent inhibitor of Ras farnesyl-protein transferase. J Am Chem Soc 1994; 116: 11606-11607
• 71 Silverman K, Cascales C, Genilloud O, Sigmund J, Gartner S, Koch G, Gagliardi M, Heimbuch BK, Nallin-Omstead M, Sanchez M, Diez M, Martin I, Garrity G, Hirsch C, Gibbs J, Singh S, Lingham R. Actinoplanic acids A and B as novel inhibitors of farnesyl-protein transferase. Appl Microbiol Biotechnol 1995; 43: 610-616
• 72 Fernandez-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer 2011; 2: 344-358
• 73 Nicolaou KC, Zhang H, Chen JS, Crawford JJ, Pasunoori L. Total synthesis and stereochemistry of uncialamycin. Angew Chem Int Ed Engl 2007; 46: 4704-4707
• 74 Bretschneider H, Hohenlohe-Oehringen K, Rhomberg A. 3-acetyl-cinchoninic acid compounds. US Patent 3311632, 1967
• 75 Fujii A, Hashiguchi S, Uematsu N, Ikariya T, Noyori R. Ruthenium(II)-catalyzed asymmetric transfer hydrogenation of ketones using a formic acid−triethylamine mixture. J Am Chem Soc 1996; 118: 2521-2522
• 76 Noyori R, Hashiguchi S. Asymmetric transfer hydrogenation catalyzed by chiral ruthenium complexes. Acc Chem Res 1997; 30: 97-102
• 77 Desrat S, van de Weghe P. Intramolecular imino Diels-Alder reaction: progress toward the synthesis of uncialamycin. J Org Chem 2009; 74: 6728-6734
• 78 Desrat S, Jean M, van de Weghe P. Setbacks and hopes: en route to the synthesis of uncialamycin. Tetrahedron 2011; 67: 7510-7516
• 79 Prasad K, Lee GT, Chaudhary A, Girgis MJ, Streemke JW, Repič O. Design of new reaction conditions for the Sugasawa reaction based on mechanistic insights. Org Process Res Dev 2003; 7: 723-732
• 80 Bartoszewicz A, Kalek M, Stawinski J. Iodine-promoted silylation of alcohols with silyl chlorides. Synthetic and mechanistic studies. Tetrahedron 2008; 64: 8843-8850
• 81 Myers AG, Tom NJ, Fraley ME, Cohen SB, Madar DJ. A convergent synthetic route to (+)-dynemicin A and analogs of wide structural variability. J Am Chem Soc 1997; 7863: 6072-6094