Secondary Metabolism of Predatory Bacteria (until 2016)

We conduct research on new antimicrobial drugs

  • Antibiotics from predatory bacteria
  • Bacterial pests and their natural products
  • Genome mining-based drug discovery
  • Molecular principles of biosynthesis
  • Biotechnological production

Antimicrobial drugs are of major significance. In the field of medicine, they are indispensable for the treatment of life-threatening infections. In the food industry, they serve as preserving agents and in agriculture they are used for pest control. The majority of antimicrobial compounds that are in use today derive from natural products. The importance of these biogenous substances is due to their structural diversity, on the one hand, and to their optimized affinity to biological targets, on the other.

Owing to the increasing dissemination of resistant pathogens, there is a constant need of identifying novel antimicrobial drugs. Genomic analyses of bacteria and fungi confirmed that the potential of these organisms for the production of antibiotics is far from being exhausted. In fact, microbial genomes harbor numerous biosynthetic pathways that cannot be associated with known metabolites. Our research aims at exploiting these untapped resources. We are particularly interested in two groups of microorganisms:

1) Predatory bacteria are soil dwelling organisms that form swarms of cells in order to invade other bacteria as well as fungi. The concerted release of antibiotics contributes to the killing of the prey. From a pharmaceutical perspective, predatory bacteria are hence a promising source for finding new medicinal drugs.

2) Phytopathogenic bacteria have barely been explored with regard to their chemistry. However, genomic studies suggest a distinctive ability to natural product biosynthesis.

Head

Dr. habil. Markus Nett

Phone: +49 3641 532-1297 Email: markus.nett@leibniz-hki.de

Topics

Drug discovery from predatory bacteria

Bacteria that band together in order to prey on other soil inhabitants are in the focus of our research. The formation of a pack enables these microorganisms to pursue a specific hunting strategy, which is beneficial  to all participants. While a single cell could not produce sufficient concentrations of an antibiotic to kill its prey, the concerted release of such compounds by an entire pack will have a profound effect. This form of collaboration which emerged in the course of evolution in several taxonomically distinct bacteria makes pack-forming bacteria a promising source for the finding of new, urgently needed antibiotics. Within this project, we isolate predatory bacteria from soil and freshwater habitats and we investigate them for the production of medicinally useful compounds. These studies are supported by the application of so-called genome mining strategies.

Novel bacterial siderophores

Siderophores are natural products, which safeguard the iron supply of microorganisms. These compounds have attracted a lot of interest due to their role as virulence factors for pathogenic bacteria and fungi, as well as potential carriers for antibiotics. In addition to their medical relevance, siderophores contribute to the structuring of microbial communities in the environment. By analyzing genomic sequence data, we identify bacteria that are capable of producing structurally unprecedented siderophores. We isolate and characterize these molecules and interrogate their significance in an ecological context.

Antibiotic biosynthesis
Exploiting the substrate tolerance of an enzymatic assembly lines enables the biotechnological production of new antibiotics against human-pathogenic mycoplasmas.
Exploiting the substrate tolerance of an enzymatic assembly lines enables the biotechnological production of new antibiotics against human-pathogenic mycoplasmas.

Understanding how microorganisms assemble complex chemical molecules opens up a plethora of opportunities in the areas of biotechnology and medicine. We are particularly interested in the biosynthesis of antibiotics, which are promising candidates for new drugs. By applying methods of genetic engineering, combinatorial biosynthesis, and even chemical synthesis we manipulate the metabolic pathways to natural products in a rational manner. In this way, derivatives with optimized properties are generated. An example is the engineering of new antibiotics against mycoplasmas. These bacteria can cause numerous diseases in humans, for the treatment of which only few drugs are currently available.

Predation strategy of Cupriavidus necator

Cupriavidus necator is a predatory bacterium which can be found in many soil habitats. Preliminary studies showed that C. necator secretes a peptidic molecule with high affinity to copper(II) ions in the presence of prey organisms. The same compound was also proposed to play a major role in the interaction with the actinomycete Agromyces ramosus which is itself an aggressive microbial predator. Just like other actinomycetes, A. ramosus spreads via the formation of mycelia. Once a mycelial contact is established with potential prey cells, the actinomycete starts to secrete hydrolytic enzymes in order to consume these organisms. The same behaviour can be observed when A. ramosus encounters C. necator. In this particular case, however, the assaulted cells strike back. The counterattack coincides with the release of the copper-binding peptide, and it culminates in the complete killing of the actinomycete. The aim of this project is the identification and structural characterization of the copper-binding compound. Furthermore, we set out to unravel the factors, which induce the production of this compound.

Publications

2016

Korp J, Vela Gurovic MS, Nett M (2016) Antibiotics from predatory bacteria. Beilstein J Org Chem 12, 594-607. (Review) Details

Kurth C, Kage H, Nett M (2016) Siderophores as molecular tools in medical and environmental applications. Org Biomol Chem 14(35), 8212-8227. Details PubMed

Kurth C, Schieferdecker S, Athanasopoulou K, Seccareccia I, Nett M (2016) Variochelins, lipopeptide siderophores from Variovorax boronicumulans discovered by genome mining. J Nat Prod 79(4), 865-872. Details PubMed

Schaible AM, Filosa R, Krauth V, Temml V, Pace S, Garscha U, Liening S, Weinigel C, Rummler S, Schieferdecker S, Nett M, Peduto A, Collarile S, Scuotto M, Roviezzo F, Spaziano G, de Rosa M, Stuppner H, Schuster D, D'Agostino B, Werz O (2016) The 5-lipoxygenase inhibitor RF-22c potently suppresses leukotriene biosynthesis in cellulo and blocks bronchoconstriction and inflammation in vivo. Biochem Pharmacol 112, 60-71. Details PubMed

Schieferdecker S, Nett M (2016) A fast and efficient method for the preparation of the 5-lipoxygenase inhibitor myxochelin A. Tetrahedron Lett 57, 1359-1360. Details

Schwenk D, Brandt P, Blanchette R, Nett M, Hoffmeister D (2016) Unexpected metabolic versatility in a combined fungal fomannoxin/vibralactone biosynthesis. J. Nat. Prod. 79, 1407-1414. Details

Seccareccia I, Kovacs AT, Gallegos-Monterrosa R, Nett M (2016) Unraveling the predator-prey relationship of Cupriavidus necator and Bacillus subtilis. Microbiol Res 192, 231-238. Details

2015

Barnes EC, Bezerra-Gomes P, Nett M, Hertweck C (2015) Dandamycin and chandrananimycin E, benzoxazines from Streptomyces griseus. J Antibiot (Tokyo) 68, 463-468. Details PubMed

Bauer JS, Ghequire MG, Nett M, Josten M, Sahl HG, De Mot R, Gross H (2015) Biosynthetic origin of the antibiotic pseudopyronines A and B in Pseudomonas putida BW11M1. ChemBioChem 16, 2491-2497. Details

Kage H, Riva E, Parascandolo JS, Kreutzer MF, Tosin M, Nett M (2015) Chemical chain termination resolves the timing of ketoreduction in a partially reducing iterative type I polyketide synthase. Org Biomol Chem 13, 11414-11417. Details

Korp J, König S, Schieferdecker S, Dahse H-M, König G M, Werz O, Nett M (2015) Harnessing enzymatic promiscuity in myxochelin biosynthesis for the production of 5-lipoxygenase inhibitors. ChemBioChem 16, 2445-2450. Details

Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, de Bruijn I, Chooi YH, Claesen J, Coates RC, Cruz-Morales P, Duddela S, Düsterhus S, Edwards DJ, Fewer DP, Garg N, Geiger C, Gomez-Escribano JP, Greule A, Hadjithomas M, Haines AS, Helfrich EJ, Hillwig ML, Ishida K, Jones AC, Jones CS, Jungmann K, Kegler C, Kim HU, Kötter P, Krug D, Masschelein J, Melnik AV, Mantovani SM, Monroe EA, Moore M, Moss N, Nützmann HW, Pan G, Pati A, Petras D, Reen FJ, Rosconi F, Rui Z, Tian Z, Tobias NJ, Tsunematsu Y, Wiemann P, Wyckoff E, Yan X, Yim G, Yu F, Xie Y, Aigle B, Apel AK, Balibar CJ, Balskus EP, Barona-Gómez F, Bechthold A, Bode HB, Borriss R, Brady SF, Brakhage AA, Caffrey P, Cheng YQ, Clardy J, Cox RJ, De Mot R, Donadio S, Donia MS, van der Donk WA, Dorrestein PC, Doyle S, Driessen AJ, Ehling-Schulz M, Entian KD, Fischbach MA, Gerwick L, Gerwick WH, Gross H, Gust B, Hertweck C, Höfte M, Jensen SE, Ju J, Katz L, Kaysser L, Klassen JL, Keller NP, Kormanec J, Kuipers OP, Kuzuyama T, Kyrpides NC, Kwon HJ, Lautru S, Lavigne R, Lee CY, Linquan B, Liu X, Liu W, Luzhetskyy A, Mahmud T, Mast Y, Méndez C, Metsä-Ketelä M, Micklefield J, Mitchell DA, Moore BS, Moreira LM, Müller R, Neilan BA, Nett M, Nielsen J, O'Gara F, Oikawa H, Osbourn A, Osburne MS, Ostash B, Payne SM, Pernodet JL, Petricek M, Piel J, Ploux O, Raaijmakers JM, Salas JA, Schmitt EK, Scott B, Seipke RF, Shen B, Sherman DH, Sivonen K, Smanski MJ, Sosio M, Stegmann E, Süssmuth RD, Tahlan K, Thomas CM, Tang Y, Truman AW, Viaud M, Walton JD, Walsh CT, Weber T, van Wezel GP, Wilkinson B, Willey JM, Wohlleben W, Wright GD, Ziemert N, Zhang C, Zotchev SB, Breitling R, Takano E, Glöckner FO (2015) Minimum information about a biosynthetic gene cluster. Nat Chem Biol 11, 625-631. Details

Schieferdecker S, Domin N, Hoffmeier C, Bryant DA, Roth M, Nett M (2015) Structure and absolute configuration of auriculamide, a natural product from the predatory bacterium Herpetosiphon aurantiacus. Eur J Org Chem 14, 3057-3062. Details

Schieferdecker S, König S, Koeberle A, Dahse H-M, Werz O, Nett M (2015) Myxochelins target human 5-lipoxygenase. J Nat Prod 78(2), 335-338. Details PubMed

Seccareccia I, Kost C, Nett M (2015) Quantitative analysis of Lysobacter predation. Appl Environ Microbiol 81(20), 7098-7105. Details

2014

Kreutzer MF, Kage H, Herrmann J, Pauly J, Hermenau R, Müller R, Hoffmeister D, Nett M (2014) Precursor-directed biosynthesis of micacocidin derivatives with activity against Mycoplasma pneumoniae. Org Biomol Chem 12, 113-118. Details PubMed

Nett M (2014) Genome mining – concept and strategies for natural product discovery. In: Kinghorn DA, Falk H, Kobayashi J (eds.) Prog Chem Org Nat Prod 99, pp. 199-245. Springer, Switzerland. Details

Otzen C, Bardl B, Jacobsen ID, Nett M, Brock M (2014) Candida albicans utilizes a modified β-oxidation pathway for the degradation of toxic propionyl-CoA. J Biol Chem 289(12), 8151-8169. Details PubMed

Pauly J, Nett M, Hoffmeister D (2014) Ralfuranone is produced by an alternative aryl-substituted γ-lactone biosynthetic route in Ralstonia solanacearum. J Nat Prod 77, 1967-1971. Details PubMed

Schieferdecker S, Exner TE, Gross H, Roth M, Nett M (2014) New myxothiazols from the predatory bacterium Myxococcus fulvus. J Antibiot 67(7), 519-525. Details PubMed

Schieferdecker S, König S, Weigel C, Dahse HM, Werz O, Nett M (2014) Structure and Biosynthetic Assembly of Gulmirecins, Macrolide Antibiotics from the Predatory Bacterium Pyxidicoccus fallax. Chem Eur J 20, 15933-15940. Details PubMed

Schwenk D, Nett M, Dahse H-M, Horn U, Blanchette RA, Hoffmeister D (2014) Injury-induced biosynthesis of methyl-branched polyene pigments in a white-rotting basidiomycete J Nat Prod 77, 2658-2663. Details PubMed

previously

Elliott CE, Callahan DL, Schwenk D, Nett M, Hoffmeister D, Howlett BJ (2013) A gene cluster responsible for biosynthesis of phomenoic acid in the plant pathogenic fungus, Leptosphaeria maculans. Fungal Genet Biol 53, 50-58. Details PubMed

Gurovic VMS, Müller S, Domin N, Seccareccia I, Nietzsche S, Martin K, Nett M (2013) Micromonospora schwarzwaldensis sp. nov., a producer of telomycin, isolated from soil. Int J Syst Evol Microbiol 63(Pt 10), 3812-3817. Details PubMed

Kage H, Kreutzer MF, Wackler B, Hoffmeister D, Nett M (2013) An iterative type I polyketide synthase initiates the biosynthesis of the antimycoplasma agent micacocidin. Chem Biol 20, 764-771. Details PubMed

Kersten RD, Lane AL, Nett M, Richter TK, Duggan BM, Dorrestein PC, Moore BS (2013) Bioactivity-guided genome mining reveals the lomaiviticin biosynthetic gene cluster in Salinispora tropica. Chembiochem 14(8), 955-962. Details PubMed

Pauly J, Spiteller D, Linz J, Jacobs J, Allen C, Nett M, Hoffmeister D (2013) Ralfuranone thioether production by the plant pathogen Ralstonia solanacearum. Chembiochem 14, 2169-2178. Details PubMed

Kastner S, Müller S, Natesan L, König GM, Guthke R, Nett M (2012) 4-Hydroxyphenylglycine biosynthesis in Herpetosiphon aurantiacus: a case of gene duplication and catalytic divergence. Arch Microbiol 194(6), 557-566. Details PubMed

Kreutzer MF, Kage H, Nett M (2012) Structure and biosynthetic assembly of cupriachelin, a photoreactive siderophore from the bioplastic producer Cupriavidus necator H16. J Am Chem Soc 134(11), 5415-5422. Details PubMed

Kreutzer MF, Nett M (2012) Genomics-driven discovery of taiwachelin, a lipopeptide siderophore from Cupriavidus taiwanensis. Org Biomol Chem 10(47), 9338-9343. Details PubMed

Roth M, Martin K, Zang E, Nett M, Henkel T (2012) A microfluidics-based approach to drug discovery. Biomed Tech (Berl) 57(SI-1 Track-B), 270. Details

Bohnert M, Miethbauer S, Dahse HM, Ziemen J, Nett M, Hoffmeister D (2011) In vitro cytotoxicity of melleolide antibiotics: structural and mechanistic aspects. Bioorg Med Chem Lett 21, 2003-2006. Details PubMed

Kiss H, Nett M, Domin N, Martin K, Maresca JA, Copeland A, Lapidus A, Lucas S, Berry KW, Glavina Del Rio T, Dalin E, Tice H, Pitluck S, Richardson P, Bruce D, Goodwin L, Han C, Detter JC, Schmutz J, Brettin T, Land M, Hauser L, Kyrpides NC, Ivanova N, Göker M, Woyke T, Klenk HP, Bryant DA (2011) Complete genome sequence of the filamentous gliding predatory bacterium Herpetosiphon aurantiacus type strain (114-95(T)). Stand Genomic Sci 5(3), 356-370. Details PubMed

Kreutzer MF, Kage H, Gebhardt P, Wackler B, Saluz HP, Hoffmeister D, Nett M (2011) Biosynthesis of a complex yersiniabactin-like natural product via the mic locus in phytopathogen Ralstonia solanacearum. Appl Environ Microbiol 77, 6117-6124. Details PubMed

Nett M, Hertweck C (2011) Farinamycin, a quinazoline from Streptomyces griseus. J Nat Prod 74(10), 2265-2268. Details PubMed

Udwary DW, Gontang EA, Jones AC, Jones CS, Schultz AW, Winter JM, Yang JY, Beauchemin N, Capson TL, Clark BR, Esquenazi E, Eustáquio AS, Freel K, Gerwick L, Gerwick WH, Gonzalez D, Liu WT, Malloy KL, Maloney KN, Nett M, Nunnery JK, Penn K, Prieto-Davo A, Simmons TL, Weitz S, Wilson MC, Tisa LS, Dorrestein PC, Moore BS (2011) Significant natural product biosynthetic potential of actinorhizal symbionts of the genus frankia, as revealed by comparative genomic and proteomic analyses. Appl Environ Microbiol 77(11), 3617-3625. Details PubMed

Wackler B, Schneider P, Jacobs JM, Pauly J, Allen C, Nett M, Hoffmeister D (2011) Ralfuranone biosynthesis in Ralstonia solanacearum suggests functional divergence in the quinone synthetase family of enzymes. Chem Biol 18, 354-360. Details PubMed

Gomes PB, Nett M, Dahse H-M, Sattler I, Martin K, Hertweck C (2010) Bezerramycins A-C, antiproliferative phenoxazinones from Streptomyces griseus featuring carboxy, carboxamide or nitrile substituents Eur J Org Chem , 231-235. Details

Gomes PB, Nett M, Dahse HM, Hertweck C (2010) Pitucamycin: structural merger of a phenoxazinone with an epoxyquinone antibiotic. J Nat Prod 73(9), 1461-1464. Details PubMed

Nett M, Gulder TA, Kale AJ, Hughes CC, Moore BS (2009) Function-oriented biosynthesis of beta-lactone proteasome inhibitors in Salinispora tropica. J Med Chem 52(19), 6163-6167. Details PubMed

Nett M, Ikeda H, Moore BS (2009) Genomic basis for natural product biosynthetic diversity in the actinomycetes. Nat Prod Rep 26(11), 1362-1384. (Review) Details PubMed

Nett M, Moore BS (2009) Exploration and engineering of biosynthetic pathways in the marine actinomycete Salinispora tropica Pure Appl Chem 81(6), 1075-1084. (Review) Details

Penn K, Jenkins C, Nett M, Udwary DW, Gontang EA, McGlinchey RP, Foster B, Lapidus A, Podell S, Allen EE, Moore BS, Jensen PR (2009) Genomic islands link secondary metabolism to functional adaptation in marine Actinobacteria. ISME J 3(10), 1193-1203. Details PubMed

Schneider P, Jacobs JM, Neres J, Aldrich CC, Allen C, Nett M, Hoffmeister D (2009) The global virulence regulators VsrAD and PhcA control secondary metabolism in the plant pathogen Ralstonia solanacearum. Chembiochem 10, 2730-2732. Details PubMed

McGlinchey RP, Nett M, Eustáquio AS, Asolkar RN, Fenical W, Moore BS (2008) Engineered biosynthesis of antiprotealide and other unnatural salinosporamide proteasome inhibitors. J Am Chem Soc 130(25), 7822-7823. Details PubMed

McGlinchey RP, Nett M, Moore BS (2008) Unraveling the biosynthesis of the sporolide cyclohexenone building block. J Am Chem Soc 130(8), 2406-2407. Details PubMed

Nett M, König GM (2007) The chemistry of gliding bacteria. Nat Prod Rep 24(6), 1245-1261. (Review) Details PubMed

Nett M, Erol O, Kehraus S, Köck M, Krick A, Eguereva E, Neu E, König GM (2006) Siphonazole, an unusual metabolite from Herpetosiphon sp. Angew Chem Int Ed Engl 45(23), 3863-3867. Details PubMed

Gross H, Kehraus S, Nett M, König GM, Beil W, Wright AD (2003) New cytotoxic cembrane based diterpenes from the soft corals Sarcophyton cherbonnieri and Nephthea sp. Org Biomol Chem 1(6), 944-949. Details PubMed