2022-04-19 ワシントン大学セントルイス
Scientists led by Joshua Blodgett in Arts & Sciences discovered a potential candidate for drug development from the soil bacterium Lentzea flaviverrucosa. (Photo: Sean Garcia)
ワシントン大学セントルイス校とハワイ大学の研究者らは、このような微生物の1つである土壌細菌「Lentzea flaviverrucosa」から、医薬品開発の候補となる物質を発見した。この研究成果は、4月19日発行の『米国科学アカデミー紀要』に掲載された
<関連情報>
- https://source.wustl.edu/2022/04/from-rare-soil-microbe-a-new-antibiotic-candidate/
- https://www.pnas.org/doi/abs/10.1073/pnas.2117941119
Lentzea flaviverrucosa DSM 44664生合成スーパークラスターがコードする珍しい二量体ピペラジルシクロペプチドの発見 Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster
Chunshun Li, Yifei Hu, Xiaohua Wu,Spencer D. Stumpf, Yunci Qi, John M. D’Alessandro, Keshav K. Nepal , Ariel M. Sarotti, Shugeng , and Joshua A. V. Blodgett
Proceedings of the National Academy of Sciences of the United States of America Published:April 19, 2022
DOI:https://doi.org/10.1073/pnas.2117941119
Abstract
Rare actinomycetes represent an underexploited source of new bioactive compounds. Here, we report the use of a targeted metabologenomic approach to identify piperazyl compounds in the rare actinomycete Lentzea flaviverrucosa DSM 44664. These efforts to identify molecules that incorporate piperazate building blocks resulted in the discovery and structural elucidation of two dimeric biaryl-cyclohexapeptides, petrichorins A and B. Petrichorin B is a symmetric homodimer similar to the known compound chloptosin, but petrichorin A is unique among known piperazyl cyclopeptides because it is an asymmetric heterodimer. Due to the structural complexity of petrichorin A, solving its structure required a combination of several standard chemical methods plus in silico modeling, strain mutagenesis, and solving the structure of its biosynthetic intermediate petrichorin C for confident assignment. Furthermore, we found that the piperazyl cyclopeptides comprising each half of the petrichorin A heterodimer are made via two distinct nonribosomal peptide synthetase (NRPS) assembly lines, and the responsible NRPS enzymes are encoded within a contiguous biosynthetic supercluster on the L. flaviverrucosa chromosome. Requiring promiscuous cytochrome p450 crosslinking events for asymmetric and symmetric biaryl production, petrichorins A and B exhibited potent in vitro activity against A2780 human ovarian cancer, HT1080 fibrosarcoma, PC3 human prostate cancer, and Jurkat human T lymphocyte cell lines with IC50 values at low nM levels. Cyclic piperazyl peptides and their crosslinked derivatives are interesting drug leads, and our findings highlight the potential for heterodimeric bicyclic peptides such as petrichorin A for inclusion in future pharmaceutical design and discovery programs.
