Synthetic Sansanmycin Analogues as Potent <i>Mycobacterium tuberculosis</i> Translocase I Inhibitors
Wendy Tran, Ali S. Kusay, Paige M. E. Hawkins, Chen‐Yi Cheung, Gayathri Nagalingam, Venugopal Pujari, Daniel Ford, Alexander Stoye, Jessica L. Ochoa, Rebecca E. Audette, Elinor Hortle, Stefan H. Oehlers, Susan A. Charman, Roger G. Linington, Eric J. Rubin, Christopher G. Dowson, David I. Roper, Dean C. Crick, Thomas Balle, Gregory M. Cook, Warwick J. Britton, Richard J. Payne
Abstract
Herein, we report the design and synthesis of inhibitors of Mycobacterium tuberculosis (Mtb) 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 Mtb MurX and potent activity against Mtb in vitro. 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 Mtb growth in macrophages where mycobacteria reside in vivo and reduced mycobacterial burden in an in vivo zebrafish model of tuberculosis.