Edith Neu

Marine Myxobacteria as a Source of Antibiotics—Comparison of Physiology, Polyketide-Type Genes and Antibiotic Production of Three New Isolates of Enhygromyxa salina

Three myxobacterial strains, designated SWB004, SWB005 and SWB006, were obtained from beach sand samples from the Pacific Ocean and the North Sea. The strains were cultivated in salt water containing media and subjected to studies to determine their taxonomic status, the presence of genes for the biosynthesis of polyketides and antibiotic production. 16S rDNA sequence analysis revealed the type strain Enhygromyxa salina SHK-1T as their closest homolog, displaying between 98% (SWB005) and 99% (SWB004 and SWB006) sequence similarity. All isolates were rod-shaped cells showing gliding motility and fruiting body formation as is known for myxobacteria. They required NaCl for growth, with an optimum concentration of around 2% [w/v]. The G + C-content of genomic DNA ranged from 63.0 to 67.3 mol%. Further, the strains were analyzed for their potential to produce polyketide-type structures. PCR amplified ketosynthase-like gene fragments from all three isolates enhances the assumption that these bacteria produce polyketides. SWB005 was shown to produce metabolites with prominent antibacterial activity, including activity towards methicillin resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE).

Salimyxins and Enhygrolides: Antibiotic, Sponge-Related Metabolites from the Obligate Marine Myxobacterium Enhygromyxa salina

Unlike their terrestrial counterparts, marine myxobacteria are hardly investigated for their secondary metabolites. This study describes three new compounds (1–3), named salimyxins and enhygrolides, obtained from the obligate marine myxobacterium Enhygromyxa salina. These are the first natural products obtained from Enhygromyxa species. Their structures were elucidated by spectroscopic analysis, including NMR and CD spectroscopy. Enhygrolides are closely related to the nostoclides, which were initially isolated from a cyanobacterium of the genus Nostoc. The salimyxins, representing structurally most unusual degraded sterols, are close to identical to demethylincisterol from the sponge Homaxinella sp. Salimyxin B and enhygrolide A inhibit the growth of the Gram‐positive bacterium Arthrobacter cristallopoietes (MIC salimyxin B, 8 μg mL−1; enhygrolide A, 4 μg mL−1).

Salimabromide: Unexpected Chemistry from the Obligate Marine Myxobacterium Enhygromxya salina

Marine myxobacteria (Enhygromyxa, Plesiocystis, Pseudoenhygromyxa, Haliangium) are phylogenetically distant from their terrestrial counterparts. Salimabromide is the first natural product from the Plesiocystis/Enhygromyxa clade of obligatory marine myxobacteria. Salimabromide has a new tetracyclic carbon skeleton, comprising a brominated benzene ring, a furano lactone residue, and a cyclohexane ring, bridged by a seven-membered cyclic moiety. The absolute configuration was deduced from experimental and calculated CD data. Salimabromide revealed antibiotic activity towards Arthrobacter cristallopoietes.

Antibiotics from gliding bacteria

In recent years the discovery of some most important antibiotic compounds obtained by fermenting environmental microbes has been reported, providing proof that isolation and fermentation of producer strains is a significant approach to decifer novel structural types of antibiotics. Whereas many microbial taxa and environments have been well investigated in the past (e.g. soil-borne actinomycetes), the high diversity of microbial populations in certain habitats, e.g. marine sediments, has to date only been exploited marginally. Myxobacteria, the most prominent class of gliding bacteria, are well known for their ability to produce structurally intriguing natural products; however, so far no myxobacterial antibiotic has been developed for clinical use. In our studies, the antibacterial activity of the myxobacterial metabolite corallopyronin A was further investigated. Feeding studies with labeled precursors allowed to deduce all building blocks for the formation of corallopyronin A, whereby its biosynthesis from two chains probably connected by a Claisen-type reaction and the incorporation of bicarbonate into the methyl carbamate functionality can be regarded as unusual characteristics. A trans-AT type mixed PKS/NRPS gene cluster containing a β-branching cassette was identified as the putative basis for corallopyronin A biosynthesis in Corallococcus coralloides. Our research also resulted in the cultivation of several unusual marine myxobacteria which produce antibiotically active molecules.

Corallorazines from the myxobacterium Corallococcus coralloides.

The myxobacterium Corallococcus coralloides is the producer of the antibiotic compound corallopyronin A, which is currently in preclinical evaluation. To obtain suitable amounts of this antibiotic, the production strain C. coralloides B035 was cultured in large volumes, which in the addition to the isolation of the target molecule facilitates the detection of additional metabolites of this myxobacterial strain (corallorazines A-C). Corallorazine A is a new structural type of dipeptide composed of a dehydroalanine and a glycine moiety that are linked via a semiaminal bond, thus forming a piperazine ring. The latter is further connected via an amide bond to an unusual aliphatic acyl chain.

Insights into Structure-Activity Relationships of Bacterial RNA Polymerase Inhibiting Corallopyronin Derivatives.

The new compound precorallopyronin A is a stable precursor in the biosynthesis of the antibiotic corallopyronin A. This natural product was isolated from the producer strain Corallococcus coralloides B035. Together with various semisynthetically obtained corallopyronin A derivatives its antibacterial effects were evaluated. In combination with an X-ray crystallization model limitations of derivatization possibilities were revealed. The antibiotic potential of the novel precorallopyronin A is comparable to that of the structurally more complex corallopyronin A, which highlights that the additional chiral center is not essential for activity.