The natural products 6-deoxyerythronolide B (6dEB), erythromycin D, yersiniabactin (Ybt), and salicylate 2-O-beta-d-glucoside (SAG), representing a range of primary and secondary metabolites generated through heterologous microbial biosynthesis, were analyzed using computational metabolic engineering for the purpose of predicting improved production. Specifically, flux balance analysis allowed for the comprehensive screening of medium components and the determination of single gene deletions that resulted in improved product titers for the target compounds. Outcomes included the identification of amino acids and alternative carbon sources capable of culture medium supplementation for increased cellular production. Separately, Minimization of Metabolic Adjustment and OptForce were used to identify single gene deletion and overexpression targets, respectively, for improvements to the aforementioned biosynthetic schemes. The computational engineering predictions thus provide a starting point for experimental implementation with the goal of improving metabolic carbon flow to the compounds presented in this study, each of which possesses valuable bioactivity. (c) 2018 American Institute of Chemical Engineers