Abstract
In this study, the influence of halide ions on [7.7]paracyclophane biosynthesis in the cyanobacterium Nostoc sp. CAVN2 was investigated. In contrast to KI and KF, supplementation of the culture medium with KCl or KBr resulted not only in an increase of growth but also in an up-regulation of carbamidocyclophane production. LC-MS analysis indicated the presence of chlorinated, brominated, but also non-halogenated derivatives. In addition to 22 known cylindrocyclophanes and carbamidocyclophanes, 27 putative congeners have been detected. Nine compounds, carbamidocyclophanes M−U, were isolated, and their structural elucidation by 1D and 2D NMR experiments in combination with HRMS and ECD analysis revealed that they are brominated analogues of chlorinated carbamidocyclophanes. Quantification of the carbamidocyclophanes showed that chloride is the preferably utilized halide, but incorporation is reduced in the presence of bromide. Evaluation of the antibacterial activity of 30 [7.7]paracyclophanes and related derivatives against selected pathogenic Gram-positive and Gram-negative bacteria exhibited remarkable effects especially against methicillin- and vancomycin-resistant staphylococci and Mycobacterium tuberculosis. For deeper insights into the mechanisms of biosynthesis, the carbamidocyclophane biosynthetic gene cluster in Nostoc sp. CAVN2 was studied. The gene putatively coding for the carbamoyltransferase has been identified. Based on bioinformatic analyses, a possible biosynthetic assembly is discussed.
Highlights
Cyanobacteria have proven to be a prolific source of structurally highly diverse and biologically active secondary metabolites
Determination of the total [7.7]paracyclophane amount was based on peak area integration of compounds eluting in the range 16.0-39.5 min as well as revealing carbamidocyclophane-like UV spectra [7], and data were calculated in relation to control data, which represent samples cultivated without halogen supplement
CAVN2 resulted in a positive influence on both the growth and the biosynthesis of halogenated as well as non-halogenated carbamidocyclophanes
Summary
Cyanobacteria have proven to be a prolific source of structurally highly diverse and biologically active secondary metabolites. Since the initial report of cylindrocyclophane A from Cylindrospermum licheniforme Kützing ATCC 29204 and nostocyclophane D from Nostoc linckia (Roth) Bornet UTEX B 1932 by Moore et al in 1990 [4], 32 other naturally occurring [7.7]paracyclophanes have been published These compounds possess a remarkable symmetric hydrocarbon macrocycle consisting of two resorcinols linked by two aliphatic chains. Carbamidocyclophane derivatives, differing from other congeners by the presence of one or two carbamate moieties within the molecule, have been reported to exhibit pronounced bioactivity against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, and Mycobacterium tuberculosis [6,7] Based on these promising bioactivities, we decided to investigate the biosynthesis of carbamidocyclophanes in Nostoc sp. CAVN2 is compared in detail with the cylindrocyclophane gene clusters of the Cylindrospermum strains UTEX ‘B 2014’ and PCC 7417
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