Abstract
Genome mining of the mithramycin producer Streptomyces argillaceus ATCC 12956 revealed 31 gene clusters for the biosynthesis of secondary metabolites, and allowed to predict the encoded products for 11 of these clusters. Cluster 18 (renamed cluster arp) corresponded to a type I polyketide gene cluster related to the previously described coelimycin P1 and streptazone gene clusters. The arp cluster consists of fourteen genes, including genes coding for putative regulatory proteins (a SARP-like transcriptional activator and a TetR-like transcriptional repressor), genes coding for structural proteins (three PKSs, one aminotransferase, two dehydrogenases, two cyclases, one imine reductase, a type II thioesterase, and a flavin reductase), and one gene coding for a hypothetical protein. Identification of encoded compounds by this cluster was achieved by combining several strategies: (i) inactivation of the type I PKS gene arpPIII; (ii) inactivation of the putative TetR-transcriptional repressor arpRII; (iii) cultivation of strains in different production media; and (iv) using engineered strains with higher intracellular concentration of malonyl-CoA. This has allowed identifying six new alkaloid compounds named argimycins P, which were purified and structurally characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. Some argimycins P showed a piperidine ring with a polyene side chain (argimycin PIX); others contain also a fused five-membered ring (argimycins PIV-PVI). Argimycins PI-PII showed a pyridine ring instead, and an additional N-acetylcysteinyl moiety. These compounds seem to play a negative role in growth and colony differentiation in S. argillaceus, and some of them show weak antibiotic activity. A pathway for the biosynthesis of argimycins P is proposed, based on the analysis of proposed enzyme functions and on the structure of compounds encoded by the arp cluster.
Highlights
Natural products have been a productive source of bioactive compounds and drugs
Streptomyces argillaceus ATCC 12956 genomic DNA was subjected to 454 sequencing, yielding 512,452 paired end sequences with a mean of 340.62 nt (174.55 Mb total)
The improvement and development of sequencing technologies and bioinformatic tools has allowed the use of genome mining as a new and effective approach to discover new metabolites produced by microorganism, by activating and/or increasing production of unknown compounds encoded by cryptic biosynthesis gene clusters (Olano et al, 2014; Rutledge and Challis, 2015; Ochi, 2016)
Summary
By the mid-1990s, >50% of all new drugs were either natural products or analogs (Cragg et al, 1997). This frequency has decreased since due to the increased efforts in synthetic small molecules, while the isolation and characterization of new natural products from crude extracts remains perceived as time-consuming and labor-intensive. Natural products and their analogs still account for >40% of small molecule drugs under development (Newman and Cragg, 2016). The importance of drug development based on natural products and their analogs is, in part, associated with their structural diversity, which facilitates opening up unexplored chemical spaces (Bauer et al, 2010). The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery (Harvey et al, 2015)
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