Synthetic Sansanmycin Analogues as Potent <i>Mycobacterium tuberculosis</i> Translocase I Inhibitors.
Tran W, Kusay AS, Hawkins PME, Cheung CY, Nagalingam G, Pujari V, Ford DJ, Stoye A, Ochoa JL, Audette RE, Hortle E, Oehlers SH, Charman SA, Linington RG, Rubin EJ, Dowson CG, Roper DI, Crick DC, Balle T, Cook GM, Britton WJ, Payne RJ.
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.