Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase I Inhibitors

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 product...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-12, Vol.64 (23), p.17326-17345
Main Authors: Tran, Wendy, Kusay, Ali S, Hawkins, Paige M. E, Cheung, Chen-Yi, Nagalingam, Gayathri, Pujari, Venugopal, Ford, Daniel J, Stoye, Alexander, Ochoa, Jessica L, Audette, Rebecca E, Hortle, Elinor, Oehlers, Stefan H, Charman, Susan A, Linington, Roger G, Rubin, Eric J, Dowson, Christopher G, Roper, David I, Crick, Dean C, Balle, Thomas, Cook, Gregory M, Britton, Warwick J, Payne, Richard J
Format: Article
Language:English
Subjects:
Animals
Antitubercular Agents - pharmacology
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - chemistry
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Hydrophobic and Hydrophilic Interactions
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - enzymology
Mycobacterium tuberculosis - growth & development
Oligopeptides - chemistry
Oligopeptides - pharmacology
Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors
Transferases (Other Substituted Phosphate Groups) - chemistry
Uridine - analogs & derivatives
Uridine - chemistry
Uridine - pharmacology
Zebrafish
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c01407