Malonyl-coenzyme A is an important precursor metabolite for the biosynthesis of polyketides, fatty acids and biofuels. However, malonyl-CoA naturally synthesized in microbial hosts is consumed for the production of amino acids, fatty acids and phospholipids leaving behind only a small amount available for overproduction targets. During the past decade, computational procedures have aided many metabolic engineering efforts to design strains of bacteria and yeast that overproduce malonyl-CoA. In this regard, we present milestones achieved from an integrated computational and an experimental study aimed at improving the intracellular availability of malonyl-CoA in Escherichia coli. We deploy the recent OptForce methodology to predict a minimal set of genetic interventions that guarantees a pre-specified yield for malonyl-CoA in E. coli strain BL21 Star™. In order to validate the model predictions, we have successfully constructed a recombinant strain of E. coli that exhibits a 4-fold increase in the levels of intracellular malonyl-CoA compared to the wild-type strain. Furthermore, we demonstrate the applicability of this E. coli strain in the synthesis of plant-specific secondary metabolites (i.e., flavanones) that are promising agents in the treatment of cardiovascular disorders and diabetes. Specifically, a titer of 474 mg/L of naringenin production was observed which, so far, is the highest yield achieved in a lab-scale fermentation process.