AUTHOR=Liu Xiao-Fang , Wang Jun-Xiao , Chen Xin-Ai , Liu Yu , Li Yong-Quan 

TITLE=Activation and Characterization of Lanthomicins A–C by Promoter Engineering in Streptomyces chattanoogensis L10

JOURNAL=Frontiers in Microbiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.902990

DOI=10.3389/fmicb.2022.902990

ISSN=1664-302X

ABSTRACT=<p>The emergence of drug resistance highlights the importance of new drug discovery. Microbial secondary metabolites encoded in biosynthetic gene clusters (BGCs) are a prolific source of drugs, whereas most of these BGCs are cryptic. Thus, taking strategies to activate these cryptic BGCs is of great importance for potential drug discovery. In this work, three novel pentangular polyphenols lanthomicin A–C were identified by activating a cryptic aromatic polyketide BGC through promoter engineering combined with optimization of fermentation conditions. We further confirmed the involvement of lanthomicin (<italic>ltm</italic>) BGC in biosynthesis by CRISPR-Cpf1-assisted gene editing. Based on functional analysis of homologous genes, a putative biosynthetic pathway was proposed for the three lanthomicins. Particularly, lanthomicin A showed antiproliferative activity with IC<sub>50</sub> 0.17 μM for lung cancer cell line A-549. The discovery of lanthomicins brings new members to the pentangular polyphenol subclade of aromatic polyketide and demonstrates the potential of <italic>Streptomyces</italic> as a source for drug discovery.</p>