Genome-Guided Discovery of Antifungal Filipins from a Deep-Sea-Derived Streptomyces antibioticus

Abstract

Nine new (1−3, 5−8, 11, and 12; named filipins VI−XIV) and three known (4, 9, and 10) filipin-type polyene macrolides were isolated from the deep-sea-derived Streptomyces antibioticus OUCT16-23 using a genome-guided strategy coupled with bioassay. Their structures were elucidated based on the extensive MS and NMR spectroscopic analyses together with ECD calculations. In an antifungal assay, compounds 4, 5, and 7−10 showed different degrees of growth inhibition against Candida albicans with minimum inhibitory concentrations (MICs) of 1.56−12.5 μg/mL, by which the alkyl side-chain substitution affecting the activity was preliminarily studied. A biosynthetic pathway to 1−12 in S. antibioticus OUCT16-23 is also proposed.

Streptomyces: a natural source of anti-Candida agents

“…These are significantly less toxic to cells that have cholesterol, and still maintained potent activity against fungi. Filipin II () has a similar toxicity to filipin III, but was the most potent against C. glabratra of all the metabolites described in the review [31, 78].…”

“…In addition to these natural isolations, innovative genetic techniques such as gene inactivation and genome mining have been used to extract derivatives of Streptomyces strains, resulting in the discovery of new metabolites. This rich diversity of sources underscores the vast untapped potential of Streptomyces in the search for anti-Candida agents [31,33,[77][78][79][80].…”

“…Previously, it was assumed that Streptomyces had been exhausted as a source of bioactive compounds at the end of the last millennium. However, the greater availability of genetic sequencing technology has revealed that there is still a remarkable diversity of these antimicrobial-producing organisms in previously unexplored and unusual habitats that might provide an equally diverse array of new antifungal compounds [30, 31]. Furthermore, although Streptomyces strains were also assumed to only produce a limited amount of antibiotics per species, new molecular insights have revealed that they possess the capacity to produce 5–10 times more antibiotics through other silent or cryptic biosynthetic gene clusters (BCG) with the same genome [32, 33].…”

NMR-Metabolomic Profiling and Genome Mining Drive the Discovery of Cyclic Decapeptides from a Marine Streptomyces

“…The theoretical ECD calculations were performed using the method previously described . Each stereoisomer was subjected to geometry optimization at the B97D/TZVP level using the Gaussian 09 program.…”

“…The theoretical ECD calculations were performed using the method previously described. 36 Each stereoisomer was subjected to geometry optimization at the B97D/TZVP level using the Gaussian 09 program. The TD calculations were performed on the optimized conformers by using the long-range-corrected hybrid CAM-B3LYP.…”