<p> Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), is one of the deadliest infectious diseases. Emergence of drug resistant strains of <i>Mtb</i> and co-infection with HIV has made TB both difficult and expensive to treat. New TB therapies are needed to shorten treatment and be effective against all strains and metabolic states of the organism. Development of inhibitors of 1-deoxy-D-xylulose-5-phosphate reducto-isomerase (Dxr), an essential enzyme for <i>Mtb,</i> is a novel approach toward the development of a new TB chemotherapy. Natural product fosmidomycin inhibits Dxr and kills other organisms (<i>Plasmodium falciparum,</i> <i>Escherichia coli</i>) reliant on this enzyme. Interestingly, fosmidomycin is not effective against <i>Mtb.</i> The goals of this work are to rationally design inhibitors that will specifically inhibit <i>Mtb</i> Dxr and enhance cellular uptake. Two series of compounds were designed and synthesized. Compounds from both series inhibit <i> Mtb</i> Dxr and demonstrate enhanced whole cell activity. The synthetic and biological results of this work will be presented.</p>