AUTHOR=Robertsen Helene , Rohrer Sabrina , Kulik Andreas , Wohlleben Wolfgang , Mast Yvonne 

TITLE=Generation of lysolipin derivatives by genetic engineering

JOURNAL=Frontiers in Chemical Biology

VOLUME=3

YEAR=2024

URL=https://www.frontiersin.org/journals/chemical-biology/articles/10.3389/fchbi.2024.1445095

DOI=10.3389/fchbi.2024.1445095

ISSN=2813-530X

ABSTRACT=<p>Lysolipin I is a halogenated, polycyclic xanthone natural product belonging to the polyketide class of antibiotics, naturally produced by <italic>Streptomyces violaceoniger</italic> TÜ96 and <italic>Streptomyces tendae</italic> TÜ4042. The biosynthesis is encoded on a 43 kb-spanning biosynthetic gene cluster. Heterologous expression of the gene cluster has been established in previous work by using the cosmid 4H04, which was transferred to <italic>Streptomyces albus</italic>. In the current study, we demonstrate the optimization of production yields of therapeutically interesting lysolipin derivatives with extended activity against Gram-negatives and less cytotoxic bioactivities, respectively, by using mutated heterologous <italic>S. albus</italic> producer strains. Production yields were significantly increased by adapting cultivation conditions as well as by inactivating the transcriptional repressor gene <italic>llpRI</italic>, which lead to increased and consistent lysolipin (derivatives) production. Furthermore, cultivation of a <italic>S. albus</italic> 4H04<italic>∆llpOI</italic> mutant strain in bromide-containing fermentation medium resulted in the production of a new brominated lysolipin derivative (C<sub>28</sub>H<sub>20</sub>BrNO<sub>9</sub>).</p>