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Abstract
Summary Streptomyces sp. NTK937, producer of benzoxazole antibiotic caboxamycin, produces in addition a methyl ester derivative, O‐methylcaboxamycin. Caboxamycin cluster, comprising one regulatory and nine structural genes, has been delimited, and each gene has been individually inactivated to demonstrate its role in the biosynthetic process. The O‐methyltransferase potentially responsible for O‐methylcaboxamycin synthesis would reside outside this cluster. Five of the genes, cbxR, cbxA, cbxB, cbxD and cbxE, encoding a SARP transcriptional regulator, salicylate synthase, 3‐oxoacyl‐ACP‐synthase, ACP and amidohydrolase, respectively, have been found to be essential for caboxamycin biosynthesis. The remaining five structural genes were found to have paralogues distributed throughout the genome, capable of partaking in the process when their cluster homologue is inactivated. Two of such paralogues, cbxC’ and cbxI’, coding an AMP‐dependent synthetase‐ligase and an anthranilate synthase, respectively, have been identified. However, the other three genes might simultaneously have more than one paralogue, given that cbxF (DAHP synthase), cbxG (2,3‐dihydro‐2,3‐dihydroxybenzoate dehydrogenase) and cbxH (isochorismatase) have three, three and five putative paralogue genes, respectively, of similar function within the genome. As a result of genetic manipulation, a novel benzoxazole (3′‐hydroxycaboxamycin) has been identified in the salicylate synthase‐deficient mutant strain ΔcbxA. 3′‐hydroxycaboxamycin derives from the cross‐talk between the caboxamycin and enterobactin pathways.
Highlights
IntroductionThe chemically obtained caboxamycin methyl ester (2) (Fig. 1) has been recently reported to inhibit hepatitis C virus replication (Talley et al, 2016)
For salicylic acid (SA), two possible biosynthetic pathways were evaluated: a direct conversion from chorismate performed by a salicylate synthase as described for Irp9 in yersiniabactin biosynthesis (Kerbarh et al, 2005), a situation that has been noted in the cross-talk production of UK-1 by nataxazole producer Streptomyces sp
Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology, Microbial Biotechnology, 10, 873–885
Summary
The chemically obtained caboxamycin methyl ester (2) (Fig. 1) has been recently reported to inhibit hepatitis C virus replication (Talley et al, 2016) These activities are a small part of the wide array of pharmacological activities shown by benzoxazole scaffold-carrying molecules (Singh et al, 2015). The knowledge gathered by unravelling the caboxamycin pathway will open up the opportunity to generate novel benzoxazole derivatives with improved biological properties such as antibiotic, antifungal, cytotoxic and others. This aim might be fulfilled using different biotechnological approaches including combinatorial biosynthesis and mutasynthesis
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