Genome Mining of Marine-Derived Streptomyces sp. SCSIO 40010 Leads to Cytotoxic New Polycyclic Tetramate Macrolactams

Abstract

Polycyclic tetramate macrolactams (PTMs) biosynthetic gene cluster are widely distributed in different bacterial types, especially in Streptomyces species. The mining of the genomic data of marine-derived Streptomyces sp. SCSIO 40010 reveals the presence of a putative PTM-encoding biosynthetic gene cluster (ptm′ BGC) that features a genetic organization for potentially producing 5/5/6 type of carbocyclic ring-containing PTMs. A fermentation of Streptomyces sp. SCSIO 40010 led to the isolation and characterization of six new PTMs 1–6. Comprehensive spectroscopic analysis assigned their planar structures and relative configurations, and their absolute configurations were deduced by comparing the experimental electronic circular dichroism (ECD) spectra with the reported spectra of the known PTMs. Intriguingly, compounds 1–6 were determined to have a trans-orientation of H-10/H-11 at the first 5-membered ring, being distinct from the cis-orientation in their known PTM congeners. PTMs 1–5 displayed cytotoxicity against several cancer cell lines, with IC50 values that ranged from 2.47 to 17.68 µM.

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“…In parallel, we also measured the electronic circular dichroism (ECD) spectrum of 1 , which was found to be in excellent agreement with the calculated ECD spectrum of 5 S , 6 R , 8 R , 10 R , 11 S , 12 S , 13 R , 14 S , 16 S , 23 S , 25 S and 10- epi -HSAF ( Figure S12 ). Thus, the structure of 1 was consistent with 10- epi -HSAF ( Figure 3 A) [ 25 , 26 ].…”

“…The molecular formula of 1 was determined as C 29 H 40 N 2 O 6 by HRESIMS ([M + H] + , m/z 513.2967, calcd for 513.2973, Figure S4 ). The planar structure of 1 was determined to be the same as that of 10- epi -HSAF [ 25 , 26 ], on the basis of NMR spectroscopic data comparisons for 1 ( Table S3 ; Figures S5–S11 ) and 10- epi -HSAF [ 25 , 26 ]. The relative configurations of 1 were assigned by NOESY correlations and then compared with 10- epi -HSAF [ 25 , 26 ].…”

“…The planar structure of 1 was determined to be the same as that of 10- epi -HSAF [ 25 , 26 ], on the basis of NMR spectroscopic data comparisons for 1 ( Table S3 ; Figures S5–S11 ) and 10- epi -HSAF [ 25 , 26 ]. The relative configurations of 1 were assigned by NOESY correlations and then compared with 10- epi -HSAF [ 25 , 26 ]. Very obvious NOESY correlations of H-5/H-13, H-6/H-8, H-6/H-14, H-6/H-16, H-8/H-10, and H-10/H-12 were observed; H-10 and H-11 were assigned to be trans -oriented for 1 .…”

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“…S29 ), a stereoisomer of 10- epi -maltophilin produced by Streptomyces sp. strain SCSIO 40010, which has a similar PTM BGC to strain JV180 ( 66 ). The sums of PTM peak areas were normalized by total protein, and the relative PTM production was calculated relative to the appropriate control strain, typically JV180 rpsL .…”

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“…Moreover, two new NRPS-PKS hybrids, guangnanmycin A and weishanmycin A1, were discovered through BGC genome mining of promising anticancer drug leads leinamycin NP family ( Figure 2 A) [ 51 ], while five out of six new NRPS-PKS polycyclic tetramate macrolactams ( Figure 2 B) from the genome of Streptomyces sp. SCSIO 40,010 were identified to have cytotoxic activity [ 52 ]. In addition, a broad-spectrum antibacterial of rare sulfur-containing phosphate argolaphos B ( Figure 2 C) was discovered by mining the genomes of 10,000 actinomycetes [ 53 ].…”