Improved polyketide production in C. glutamicum by preventing propionate-induced growth inhibition

Corynebacterium glutamicum is a promising host for production of valuable polyketides. Propionate addition, a strategy known to increase polyketide production by increasing intracellular methylmalonyl-CoA availability, causes growth inhibition in C. glutamicum. The mechanism of this inhibition was unclear before our work. Here we provide evidence that accumulation of propionyl-CoA and methylmalonyl-CoA induces growth inhibition in C. glutamicum. We then show that growth inhibition can be relieved by introducing methylmalonyl-CoA-dependent polyketide synthases. With germicidin as an example, we used adaptive laboratory evolution to leverage the fitness advantage of polyketide production in the presence of propionate to evolve improved germicidin production. Whole-genome sequencing revealed mutations in germicidin synthase, which improved germicidin titer, as well as mutations in citrate synthase, which effectively evolved the native glyoxylate pathway to a new methylcitrate pathway. Together, our results show that C. glutamicum is a capable host for polyketide production and we can take advantage of propionate growth inhibition to drive titers higher using laboratory evolution or to screen for production of polyketides. Propionate addition is a common strategy for production of valuable polyketides by supplying the substrate methylmalonyl-CoA in the industrial microbe Corynebacterium glutamicum; however, propionate inhibits C. glutamicum growth, thus hampering polyketide production. In this study, Zhan et al. identify the reasons for propionate-elicited growth inhibition and metabolically engineer C. glutamicum to circumvent this roadblock and increase polyketide production.