New bacterial sources for antimicrobially active compounds
Zusammenfassung der Projektergebnisse
This project focused on terrestrial and marine myxobacteria as sources of antibiotics. From the terrestrial Corallococus coralloides B035 we obtained corallopyronin A, formerly reported by Höfle and Reichenbach. In collaboration with Prof. Hoerauf/Dr. Pfarr corallopyronin A was shown to be a potent antibacterial molecule with in vivo activity towards the endosymbiotic Wolbachia of filaria in the mouse model, with its activity being superior that of the established antibiotic doxycycline. Corallopyronin A is currently in the focus of a translational project, attempting to establish this molecule as a new antibiotic drug. Detailed studies allowed us to deduce the biosynthetic gene cluster for this polyketide/nonribosomal peptide (PKS/NRPS)-derived metabolite. Corallopyronin A biosynthesis shows some noncanonical features, (i) the core structure is formed by head to head connection of two separate chains derived from a PKS and a PKS-NRPS system, respectively, (ii) two of the methyl groups are incorporated by a β-branching cassette, and (iii) the ER functionality is encoded in trans-position as a bifunctional enzyme together with the trans-AT. Investigations with heterologously produced biosynthetic enzymes allowed to deduce the function of individual proteins of the corallopyronin A biosynthetic process. CorH catalyzes the methylation of hydrogen carbonate by S-adenosyl methionine, yielding methylated hydrogen carbonate. This is the precursor which subsequently is loaded to the carrier protein of the loading module (ACP1) of the mixed trans-PKS/NRPS enzymatic machinery of corallopyronin A biosynthesis. The latter is a unique biochemical process in natural product biosynthesis. We could also show that the first double bond in the western chain of corallopytonin A is introduced by the enzymatic activity of module 2 and subsequently isomerized by the DH* domain of module 3, before further elongation occurs. Furthermore, we determined the structure of CorB, a polyketide synthase, which is interconnecting the western and eastern chain of corallopyronin A, to high-resolution by X-ray crystallography. From C. coralloides the biosynthetic intermediate pre-corallopyronin A, missing the hydroxyl function at C-24 was isolated. This molecule also showed antimicrobial properties, however its potency was reduced when compared to corallopyronin A. Acylation of the hydroxyl group of corallopyronin A by semi-synthesis lead to inactive compounds. C. coralloides was also shown to produce new dipeptides named corallorazines. Marine myxobacteria are quite distinct from their terrestrial counterparts. Despite difficulties in cultivating these microorganisms, we were successful in isolating the unique metabolite salimabromide with a new carbon skeleton from the marine myxobacterium Enhygromyxa cf. salina. Together with the also obtained enhygrolides and salimyxins these are among the first natural products known from these sources.
Projektbezogene Publikationen (Auswahl)
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(2010). Biosynthesis of the myxobacterial antibiotic corallopyronin A, ChemBioChem 11, 1253-1265
Erol Ö, Schäberle TF, Schmitz A, Kehraus S, Piel J, Gurgui C, Rachid S, Müller R, König GM
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(2010). Marine myxobacteria as a source of antibiotics - Comparison of the physiology, polyketide-type genes and antibiotic production of three new isolates of Enhygromyxa salina. Marine Drugs 8, 2466-2479
Schäberle TF, Goralski E, Neu E, Erol Ö, Hölzl G, Dörmann P, Bierbaum G, König GM
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(2011). Antimicrobial phenalenone derivatives from the marine-derived fungus Coniothyrium cereale, Org. Biomol. Chem., 9, 802-808
Elsebai MF, Kehraus S, Lindequist U, Sasse F, Shaaban S, Gütschow M, Josten M, Sahl HG, König GM
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(2012). Corallopyronin A specifically targets and depletes essential obligate Wolbachia endobacteria from filarial nematodes in vivo. J Infect Dis., 206, 249-257
Schiefer A, Schmitz A, Schäberle TF, Specht S, Lämmer C, Johnston KL, Vassylyev DG, König GM, Hoerauf A, Pfarr K
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(2013). Salimabromide: Unexpected chemistry from the obligate marine myxobacterium Enhygromxya salina. Chemistry,19, 9319-9324
Felder S, Dreisigacker S, Kehraus S, Neu E, Bierbaum G, Menche D, Schäberle TF, König GM
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(2013). Salimyxins and Enhygrolides: Antibiotic, sponge-related metabolites from the obligate marine myxobacterium Enhygromyxa salina. ChemBioChem.,14, 1363-1371
Felder S, Kehraus S, Neu E, Bierbaum G, Schäberle TF, König GM
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(2013). α,β→β,γ Double bond migration in corallopyronin A biosynthesis. Chem. Sci., 4, 4175-4180
Lohr F, Jenniches I, Fritzler M, Meehan MJ, Sylvester M, Schmitz A, Gütschow M, Dorrestein PC, König GM, Schäberle TF
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(2014). Corallorazines from the myxobacterium Corallococcus coralloides. J. Nat. Prod., 77, 159-163
Schmitz A, Kehraus S, Neu E, Almeida C, Roth M, Schäberle TF, König GM
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(2014). Function of the loading module in CorI and of the O-methyltransferase CorH in vinyl carbamate biosynthesis of the antibiotic corallopyronin A. Antimicrob. Agents Chemother., 58, 950-956
Schäberle TF, Mir Mohseni M, Lohr F, Schmitz A, König GM
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(2015). Insights into structure activity relationships of bacterial RNA polymerase inhibiting corallopyronin derivatives. J. Nat. Prod., 78, 2505-2509
Schäberle TF, Schmitz A, Zocher G, Schiefer A, Kehraus S, Neu E, Roth M, Vassylyev DG, Stehle T, Bierbaum G, Hoerauf A, Pfarr K, König GM
