Li Su (Team 3)
Generation of analogues of the anti-tumor polyketide stambomycins by genetic engineering and allied approaches
The polyketide secondary metabolites of bacteria are a rich source of bioactive agents, with notable applications in anti-infective and anti-cancer therapy. However, their structures often need to be optimized in order to tailor their therapeutic and biophysical properties. The 51-membered macrolide stambomycins, among the largest of known polyketides, were recently discovered by genome mining in Streptomyces ambofaciens ATCC23877, and notably exhibit promising anti-cancer activity. The family encompasses six members which differ from each other in the alkyl functionality at C-26, due to the alternative choice of extender units by an exceptional acyl transferase domain (AT12) of the modular polyketide synthase (PKS) responsible for synthesizing the stambomycin core. Given their enormous size of the stambomycins and the intrinsic promiscuity of AT12, there is substantial interest in accessing ring-contracted and C-26 substituted derivatives of this compounds which might retain the bioactivity of the parental structures, or exhibit improved or even new properties.
In this work, we have leveraged our current understanding of modular PKS systems to internally contract the stambomycin assembly line, leading to the successful generation, albeit at low yield, of target smaller derivatives (37-membered ‘mini-stambomycins’). By careful analysis, we could identify multiple factors contributing to the low titers, information which should inform future engineering strategies. Furthermore, using a mutasynthesis strategy, we were able to exploit the broad specificity of the AT12 domain to create six novel C-26 substituted stambomycin analogues. Finally, we unexpectedly identified three series of novel desferrioxamine siderophores produced by S. ambofaciens. As a number of key metabolites generated in this work have potential interest for therapeutic applications, they will be targeted for purification, structural characterization and biological evaluation.
14/05/2021 – 14h00 – PhD defense (visioconference)