Herein, we report the design and synthesis of inhibitors of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) phospho-MurNAc-pentapeptide translocase I (MurX), the first membrane-associated step of peptidoglycan synthesis, leveraging the privileged structure of the sansanmycin family of uridylpeptide natural products. A number of analogues bearing hydrophobic amide modifications to the pseudo-peptidic end of the natural product scaffold were generated that exhibited nanomolar inhibitory activity against <i>Mtb</i> MurX and potent activity against <i>Mtb in vitro</i>. We show that a lead analogue bearing an appended neopentylamide moiety possesses rapid antimycobacterial effects with a profile similar to the frontline tuberculosis drug isoniazid. This molecule was also capable of inhibiting <i>Mtb</i> growth in macrophages where mycobacteria reside <i>in vivo</i> and reduced mycobacterial burden in an <i>in vivo</i> zebrafish model of tuberculosis.