Discovery of unusual dimeric piperazyl cyclopeptides encoded by a Lentzea flaviverrucosa DSM 44664 biosynthetic supercluster

LI, C.; HU, Y.; WU, X.; STUMPF, S. D. ; QI, Y.; D`ALESSANDRO, J. M. ; NEPAL, K. K.; SAROTTI, A.M.; CAO, S.*; BLODGETT, J. A. *

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2022 vol. 19 p. 1 - 10

0027-8424

Rare actinomycetes represent an underexploited source of new bioactive compounds.Here, we report the use of a targeted metabologenomic approach to identify piperazylQ: 7compounds in the rare actinomycete Lentzea flaviverrucosa DSM 44664. Theseefforts to identify molecules that incorporate piperazate building blocks resulted inthe discovery and structural elucidation of two dimeric biaryl-cyclohexapeptides, pet-richorins A and B. Petrichorin B is a symmetric homodimer similar to the knowncompound chloptosin, but petrichorin A is unique among known piperazyl cyclopep-tides because it is an asymmetric heterodimer. Due to the structural complexity ofpetrichorin A, solving its structure required a combination of several standard chemi-cal methods plus in silico modeling, strain mutagenesis, and solving the structure ofits biosynthetic intermediate petrichorin C for confident assignment. Furthermore,we found that the piperazyl cyclopeptides comprising each half of the petrichorin Aheterodimer are made via two distinct nonribosomal peptide synthetase (NRPS)assembly lines, and the responsible NRPS enzymes are encoded within a contiguousbiosynthetic supercluster on the L. flaviverrucosa chromosome. Requiring promiscu-ous cytochrome p450 crosslinking events for asymmetric and symmetric biaryl pro-duction, petrichorins A and B exhibited potent in vitro activity against A2780 humanovarian cancer, HT1080 fibrosarcoma, PC3 human prostate cancer, and Jurkathuman T lymphocyte cell lines with IC50 values at low nM levels. Cyclic piperazylpeptides and their crosslinked derivatives are interesting drug leads, and our findingshighlight the potential for heterodimeric bicyclic peptides such as petrichorin A forinclusion in future pharmaceutical design and discovery programs.