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Review
. 2024 Feb 23;87(2):439-452.
doi: 10.1021/acs.jnatprod.3c01007. Epub 2024 Feb 14.

MAR4 Streptomyces: A Unique Resource for Natural Product Discovery

Douglas Sweeney  1 , Alexander B Chase  2 , Alexander Bogdanov  1 , Paul R Jensen  1
Affiliations
Review

MAR4 Streptomyces: A Unique Resource for Natural Product Discovery

Douglas Sweeney et al. J Nat Prod. .

Abstract

Marine-derived Streptomyces have long been recognized as a source of novel, pharmaceutically relevant natural products. Among these bacteria, the MAR4 clade within the genus Streptomyces has been identified as metabolically rich, yielding over 93 different compounds to date. MAR4 strains are particularly noteworthy for the production of halogenated hybrid isoprenoid natural products, a relatively rare class of bacterial metabolites that possess a wide range of biological activities. MAR4 genomes are enriched in vanadium haloperoxidase and prenyltransferase genes, thus accounting for the production of these compounds. Functional characterization of the enzymes encoded in MAR4 genomes has advanced our understanding of halogenated, hybrid isoprenoid biosynthesis. Despite the exceptional biosynthetic capabilities of MAR4 bacteria, the large body of research they have stimulated has yet to be compiled. Here we review 35 years of natural product research on MAR4 strains and update the molecular diversity of this unique group of bacteria.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Chart 1
Chart 1. Possible Intermediates in Napyradiomycin Biosynthesisa
Chart 2
Chart 2. MAR4 A-Type Napyradiomycins
Chart 3
Chart 3. MAR4 B-Type Napyradiomycins
Chart 4
Chart 4. MAR4 C-Type and D-Type Napyradiomycins and Azamerone
Chart 5
Chart 5. Marinone Class of THN Natural Products
Chart 6
Chart 6. Unclassified THN Products Reported from MAR4 Strainsa
Chart 7
Chart 7. MAR4 Phenazine Natural Products
Chart 8
Chart 8. MAR4 α-Nitropyrrole Natural Products
Figure 1
Figure 1
Workflow used to identify MAR4 16S rRNA sequences. The results from iterative, NCBI database searches were dereplicated and used to generate preliminary phylogenies. Candidate MAR4 sequences were used as queries to repeat the search process until no new sequences were identified. The final phylogeny (Figure S1) revealed a monophyletic clade consisting of 326 MAR4 sequences.
Figure 2
Figure 2
MAR4 16S phylogeny generated using centroid sequences (98% clustering). Red lines demarcate the MAR4 clade. The S. aculeolatus and S. synnematoformans clades, which account for 167 and 14 of the sequences, respectively, have been collapsed. The 10 most closely related Streptomyces species are included for reference. Bootstrap values are shown as red triangles. * indicates the basal node that defines the MAR4 clade.
Figure 3
Figure 3
Global distribution and source of MAR4 strains. Pie charts represent isolation source from each location; yellow borders indicate strains with genome sequences. Location and number of strains are indicated.
Chart 9
Chart 9. MAR4 Actinofuranone Natural Products
Chart 10
Chart 10. Structures of Tetronomycin and Tetronasin
Chart 11
Chart 11. Chromenone Natural Products from MAR4 Strain CNQ-031a
Figure 4
Figure 4
MAR4 multigene phylogeny and BGC distribution. (A) Multigene phylogeny delineates six <95% ANI clades (first column indicated by color). Clades correlated to S. synnematoformans (Syn.) and S. aculeolatus (Acu.) are indicated. The distributions of experimentally characterized BGCs (known) and those with predicted products (unknown) are presented as a presence/absence table. Black indicates the presence of the BGC, but compound production is not reported; green indicates both the presence of the BGC and compound production reported; red indicates the detection of compounds that have not been linked to a BGC. (B) BiG-SCAPE network of BGCs identified from MAR4 genomes. Nodes are colored by ANI species group; gray nodes are MIBiG reference BGCs. Nodes with red borders represent BGCs on contig edges. The seven MIBiG BGC families are boxed in red dashes. Singleton BGCs were omitted.
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