Engineering of polyketide synthase leads to ‘low-fat’ stambomycins Li Su 1 , Laurence Hôtel 2, Cédric Paris 2 , Clara Chepkirui 3 , Alexander O. Brachmann 3 , Jörn Piel 3 , Christophe Jacob 2 , Bertrand Aigle 2 ,Kira J. Weissman 2 1 Max-Planck-Institute for Terrestrial Microbiology, Germany, 2 Université de Lorraine, France, 3 ETH Zurich, Switzerland Bacterial polyketide secondary metabolites exhibit a wide range of useful biological activities, including antibiotic, antifungal, anti-tumor and immunosuppressive properties. Although in some cases it is possible to use polyketides directly in their natural form, in other instances, it is necessary to adapt the molecules’ physical and medicinal properties so they function better in our bodies. Remarkably, work on certain polyketides has even demonstrated that large portions of the structures are superfluous, and thus that simplified versions can be just as effective as the parent molecules 1 . This is perhaps not surprising when you consider that the molecules did not evolve to work in human and animal bodies, but rather for bacterial purposes such as defense and signaling in the soil and the sea. In our study, we aimed to show that a module-based engineering approach could be used to produce structurally- simplified polyketides. For this, we targeted a PKS system giving rise to some of the largest of all known polyketides – the 51-membered anti-cancer stambomycins – in the soil bacterium Streptomyces ambofaciens 2 . In particular, we set out to remove 7 whole modules from the assembly line, to generate a series of ‘low-fat’ 37-membered mini-stambomycins. By testing various state-of-the-art strategies, including varying the domain composition of the modules, we ultimately succeeded in making the target mini-stambomycins, at yields only 8-fold reduced relative to the wild type stambomycins 3 . Our results thus allowed us to identify factors that influence the efficiency of such engineering, as well as areas for further improvement. In conclusion, we hope that these results will be of utility for future efforts by the polyketide community to force other over-sized polyketides to lose weight. References 1. Wang, S. et al. (2019) Structural simplification of natural products. Chem. Rev. 119 , 4180–4220. 2. Laureti, L., et al. (2011) Identification of a bioactive 51-membered macrolide complex by activation of a silent polyketide synthase in Streptomyces ambofaciens . Proc. Natl. Acad. Sci. USA 108 , 6258–6263. 3. Su L. et al., (2022) Engineering the stambomycin modular polyketide synthase yields 37-membered mini-stambomycins, https://doi.org/10.1038/s41467-022-27955-z, Nat. Commun. , in print.
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