Exploring the Biocombinatorial Potential of Benzoxazoles: Generation of Novel Caboxamycin Derivatives

Overview

Journal Microb Cell Fact

Publisher Biomed Central

Specialties Biotechnology
Microbiology

Date 2017 May 27

PMID 28545544

Citations 2

Authors

Armando A Losada

Carmen Mendez

Jose A Salas

Carlos Olano

Affiliations

Soon will be listed here.

Abstract

Background: The biosynthesis pathway of benzoxazole compounds caboxamycin and nataxazole have been recently elucidated. Both compounds share one of their precursors, 3-hydroxyanthranilate (two units in the case of nataxazole). In addition, caboxamycin structure includes a salicylate moiety while 6-methylsalycilate is the third scaffold in nataxazole. Pathways cross-talk has been identified in caboxamycin producer Streptomyces sp. NTK937, between caboxamycin and enterobactin pathways, and nataxazole producer Streptomyces sp. Tü6176, between nataxazole and coelibactin pathways. These events represent a natural form of combinatorial biosynthesis.

Results: Eleven novel caboxamycin derivatives, and five putative novel derivatives, bearing distinct substitutions in the aryl ring have been generated. These compounds were produced by heterologous expression of several caboxamycin biosynthesis genes in Streptomyces albus J1074 (two compounds), by combinatorial biosynthesis in Streptomyces sp. NTK937 expressing nataxazole iterative polyketide synthase (two compounds) and by mutasynthesis using a nonproducing mutant of Streptomyces sp. NTK937 (12 compounds). Some of the compounds showed improved bioactive properties in comparison with caboxamycin.

Conclusions: In addition to the benzoxazoles naturally biosynthesized by the caboxamycin and nataxazole producers, a greater structural diversity can be generated by mutasynthesis and heterologous expression of benzoxazole biosynthesis genes, not only in the respective producer strains but also in non-benzoxazole producers such as S. albus strains. These results show that the production of a wide variety of benzoxazoles could be potentially achieved by the sole expression of cbxBCDE genes (or orthologs thereof), supplying an external source of salicylate-like compounds, or with the concomitant expression of other genes capable of synthesizing salicylates, such as cbxA or natPK.

Citing Articles

Genomics-Driven Discovery of Benzoxazole Alkaloids from the Marine-Derived sp. SCSIO 07395.

Cheng Z, Zhang Q, Peng J, Zhao X, Ma L, Zhang C Molecules. 2023; 28(2).

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New Sipanmycin Analogues Generated by Combinatorial Biosynthesis and Mutasynthesis Approaches Relying on the Substrate Flexibility of Key Enzymes in the Biosynthetic Pathway.

Malmierca M, Perez-Victoria I, Martin J, Reyes F, Mendez C, Salas J Appl Environ Microbiol. 2019; 86(3).

PMID: 31732573 PMC: 6974644. DOI: 10.1128/AEM.02453-19.

References

Menendez N, Nur-E-Alam M, Fischer C, Brana A, Salas J, Rohr J . Deoxysugar transfer during chromomycin A3 biosynthesis in Streptomyces griseus subsp. griseus: new derivatives with antitumor activity. Appl Environ Microbiol. 2006; 72(1):167-77. PMC: 1352227. DOI: 10.1128/AEM.72.1.167-177.2006. View

Morollo A, Bauerle R . Characterization of composite aminodeoxyisochorismate synthase and aminodeoxyisochorismate lyase activities of anthranilate synthase. Proc Natl Acad Sci U S A. 1993; 90(21):9983-7. PMC: 47697. DOI: 10.1073/pnas.90.21.9983. View

Losada A, Cano-Prieto C, Garcia-Salcedo R, Brana A, Mendez C, Salas J . Caboxamycin biosynthesis pathway and identification of novel benzoxazoles produced by cross-talk in Streptomyces sp. NTK 937. Microb Biotechnol. 2017; 10(4):873-885. PMC: 5481532. DOI: 10.1111/1751-7915.12716. View

Gonzalez A, Rodriguez M, Brana A, Mendez C, Salas J, Olano C . New insights into paulomycin biosynthesis pathway in Streptomyces albus J1074 and generation of novel derivatives by combinatorial biosynthesis. Microb Cell Fact. 2016; 15:56. PMC: 4802897. DOI: 10.1186/s12934-016-0452-4. View

Gou L, Wu Q, Lin S, Li X, Liang J, Zhou X . Mutasynthesis of pyrrole spiroketal compound using calcimycin 3-hydroxy anthranilic acid biosynthetic mutant. Appl Microbiol Biotechnol. 2013; 97(18):8183-91. DOI: 10.1007/s00253-013-4882-1. View

Goswami A, Van Lanen S . Enzymatic strategies and biocatalysts for amide bond formation: tricks of the trade outside of the ribosome. Mol Biosyst. 2014; 11(2):338-53. PMC: 4304603. DOI: 10.1039/c4mb00627e. View

Cano-Prieto C, Losada A, Brana A, Mendez C, Salas J, Olano C . Crosstalk of Nataxazole Pathway with Chorismate-Derived Ionophore Biosynthesis Pathways in Streptomyces sp. Tü 6176. Chembiochem. 2015; 16(13):1925-1932. DOI: 10.1002/cbic.201500261. View

Tipparaju S, Joyasawal S, Pieroni M, Kaiser M, Brun R, Kozikowski A . In pursuit of natural product leads: synthesis and biological evaluation of 2-[3-hydroxy-2-[(3-hydroxypyridine-2-carbonyl)amino]phenyl]benzoxazole-4-carboxylic acid (A-33853) and its analogues: discovery of N-(2-benzoxazol-2-ylphenyl)benzamides as.... J Med Chem. 2008; 51(23):7344-7. DOI: 10.1021/jm801241n. View

Lv M, Zhao J, Deng Z, Yu Y . Characterization of the Biosynthetic Gene Cluster for Benzoxazole Antibiotics A33853 Reveals Unusual Assembly Logic. Chem Biol. 2015; 22(10):1313-24. DOI: 10.1016/j.chembiol.2015.09.005. View

10.

Ward D, Talley D, Tavag M, Menji S, Schaughency P, Baier A . UK-1 and structural analogs are potent inhibitors of hepatitis C virus replication. Bioorg Med Chem Lett. 2013; 24(2):609-12. PMC: 6136245. DOI: 10.1016/j.bmcl.2013.12.012. View

11.

Wu Q, Liang J, Lin S, Zhou X, Bai L, Deng Z . Characterization of the biosynthesis gene cluster for the pyrrole polyether antibiotic calcimycin (A23187) in Streptomyces chartreusis NRRL 3882. Antimicrob Agents Chemother. 2010; 55(3):974-82. PMC: 3067094. DOI: 10.1128/AAC.01130-10. View

12.

Cano-Prieto C, Garcia-Salcedo R, Sanchez-Hidalgo M, Brana A, Fiedler H, Mendez C . Genome Mining of Streptomyces sp. Tü 6176: Characterization of the Nataxazole Biosynthesis Pathway. Chembiochem. 2015; 16(10):1461-73. DOI: 10.1002/cbic.201500153. View

13.

Bibb M, Janssen G, Ward J . Cloning and analysis of the promoter region of the erythromycin resistance gene (ermE) of Streptomyces erythraeus. Gene. 1985; 38(1-3):215-26. DOI: 10.1016/0378-1119(85)90220-3. View

14.

Michel K, Boeck L, HOEHN M, Jones N, Chaney M . The discovery, fermentation, isolation, and structure of antibiotic A33853 and its tetraacetyl derivative. J Antibiot (Tokyo). 1984; 37(5):441-5. DOI: 10.7164/antibiotics.37.441. View

15.

Wilkinson B, Gregory M, Moss S, Carletti I, Sheridan R, Kaja A . Separation of anti-angiogenic and cytotoxic activities of borrelidin by modification at the C17 side chain. Bioorg Med Chem Lett. 2006; 16(22):5814-7. DOI: 10.1016/j.bmcl.2006.08.073. View

16.

Olano C, Mendez C, Salas J . Molecular insights on the biosynthesis of antitumour compounds by actinomycetes. Microb Biotechnol. 2011; 4(2):144-64. PMC: 3818856. DOI: 10.1111/j.1751-7915.2010.00231.x. View

17.

Light S, Anderson W . The diversity of allosteric controls at the gateway to aromatic amino acid biosynthesis. Protein Sci. 2013; 22(4):395-404. PMC: 3610045. DOI: 10.1002/pro.2233. View

18.

Gazzaniga F, Stebbins R, Chang S, McPeek M, Brenner C . Microbial NAD metabolism: lessons from comparative genomics. Microbiol Mol Biol Rev. 2009; 73(3):529-41, Table of Contents. PMC: 2738131. DOI: 10.1128/MMBR.00042-08. View

19.

Sommer P, Almeida R, Schneider K, Beil W, Sussmuth R, Fiedler H . Nataxazole, a new benzoxazole derivative with antitumor activity produced by Streptomyces sp. Tü 6176. J Antibiot (Tokyo). 2009; 61(11):683-6. DOI: 10.1038/ja.2008.97. View

20.

Olano C, Garcia I, Gonzalez A, Rodriguez M, Rozas D, Rubio J . Activation and identification of five clusters for secondary metabolites in Streptomyces albus J1074. Microb Biotechnol. 2014; 7(3):242-56. PMC: 3992020. DOI: 10.1111/1751-7915.12116. View