Discovery of Unprecedented Arylation Coupling Cyclopeptide Inspires Natural Product-like Antitubercular Lead Compounds

Tuberculosis (TB)
remains one of the world’s deadliest
communicable
diseases. Naturally derived antibiotics appear frequently in nature
as collections of structurally similar compounds representing an adaptive
evolutionary response to drug resistance development. Herein, we report
an undescribed versicomycin (1), featuring an unprecedented
post-nonribosomal peptide synthetase (NRPS) assembly line-modified
skeleton, which was isolated from the marine-derived fungus. Gram-scale
total synthesis of versicomycin (1) was accomplished
using a hybrid synthesis strategy combining solid-phase chemistry,
solution-phase cyclization, and chemical C–H bond functionalization.
Inspired by this undescribed natural product (NP) skeleton, we efficiently
developed a compound library comprising 89 natural product-like cycloheptapeptides
(2–90) bearing aryl groups. Their
antituberculosis activity, structure–activity relationships
(SARs), and conformational effects along with in vitro and in vivo antibacterial effects were evaluated
using Mycobacterium marinum. Remarkably,
CHNQD-02353 (21), the most potent candidate, suppressed
the proliferation of Mycobacterium tuberculosis H37Ra effectively with an MIC90 value of 0.25 μM,
which is 300-fold lower than that of versicomycin (1).
The in vitro study demonstrated that CHNQD-02353
exhibited biocompatibility and synergistic effects with major frontline
drugs, indicating its broad clinical application potential. Further
subcutaneous M. marinum infection study
in mice revealed that CHNQD-02353 cleared bacteria effectively from
lesions, demonstrating its in vivo anti-infective
potential. These results show that our integrated research strategy
has discovered a structurally untapped chemical class, representing
a promising new area for antibiotic drug discovery.