Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase I Inhibitors.

Tran, W; Kusay, AS; Hawkins, PME; Cheung, C-Y; 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

Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase I Inhibitors.

Tran, W Kusay, AS Hawkins, PME Cheung, C-Y 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

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Publisher:: American Chemical Society
Publication Type:: Journal Article
Citation:: Journal of Medicinal Chemistry, 2021, 64, (23), pp. 17326-17345
Issue Date:: 2021-12-09

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Field	Value	Language
dc.contributor.author	Tran, W
dc.contributor.author	Kusay, AS
dc.contributor.author	Hawkins, PME
dc.contributor.author	Cheung, C-Y
dc.contributor.author	Nagalingam, G
dc.contributor.author	Pujari, V
dc.contributor.author	Ford, DJ
dc.contributor.author	Stoye, A
dc.contributor.author	Ochoa, JL
dc.contributor.author	Audette, RE
dc.contributor.author	Hortle, E https://orcid.org/0000-0001-9633-5638
dc.contributor.author	Oehlers, SH
dc.contributor.author	Charman, SA
dc.contributor.author	Linington, RG
dc.contributor.author	Rubin, EJ
dc.contributor.author	Dowson, CG
dc.contributor.author	Roper, DI
dc.contributor.author	Crick, DC
dc.contributor.author	Balle, T
dc.contributor.author	Cook, GM
dc.contributor.author	Britton, WJ
dc.contributor.author	Payne, RJ
dc.date.accessioned	2022-02-16T04:57:09Z
dc.date.available	2022-02-16T04:57:09Z
dc.date.issued	2021-12-09
dc.identifier.citation	Journal of Medicinal Chemistry, 2021, 64, (23), pp. 17326-17345
dc.identifier.issn	0022-2623
dc.identifier.issn	1520-4804
dc.identifier.uri	http://hdl.handle.net/10453/154606
dc.description.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.
dc.language	eng
dc.publisher	American Chemical Society
dc.relation.ispartof	Journal of Medicinal Chemistry
dc.relation.isbasedon	10.1021/acs.jmedchem.1c01407
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences
dc.subject.classification	Medicinal & Biomolecular Chemistry
dc.subject.mesh	Animals
dc.subject.mesh	Antitubercular Agents
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Hydrophobic and Hydrophilic Interactions
dc.subject.mesh	Mycobacterium tuberculosis
dc.subject.mesh	Oligopeptides
dc.subject.mesh	Transferases (Other Substituted Phosphate Groups)
dc.subject.mesh	Uridine
dc.subject.mesh	Zebrafish
dc.subject.mesh	Animals
dc.subject.mesh	Antitubercular Agents
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Enzyme Inhibitors
dc.subject.mesh	Hydrophobic and Hydrophilic Interactions
dc.subject.mesh	Mycobacterium tuberculosis
dc.subject.mesh	Oligopeptides
dc.subject.mesh	Transferases (Other Substituted Phosphate Groups)
dc.subject.mesh	Uridine
dc.subject.mesh	Zebrafish
dc.title	Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase I Inhibitors.
dc.type	Journal Article
utslib.citation.volume	64
utslib.location.activity	United States
utslib.for	0304 Medicinal and Biomolecular Chemistry
utslib.for	0305 Organic Chemistry
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-02-16T04:57:05Z
pubs.issue	23
pubs.publication-status	Published
pubs.volume	64
utslib.citation.issue	23

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.

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http://hdl.handle.net/10453/154606