Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase i Inhibitors

Wendy Tran; Ali S. Kusay; Paige M.E. Hawkins; Chen Yi Cheung; Gayathri Nagalingam; Venugopal Pujari; Daniel J. 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

doi:10.1021/acs.jmedchem.1c01407

Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase i Inhibitors

Wendy Tran, Ali S. Kusay, Paige M.E. Hawkins, Chen Yi Cheung, Gayathri Nagalingam, Venugopal Pujari, Daniel J. 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. CookWarwick J. Britton, Richard J. Payne

Centre for Drug Candidate Optimisation

Research output: Contribution to journal › Article › Research › peer-review

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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.

Original language	English
Pages (from-to)	17326-17345
Number of pages	20
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	23
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01407
Publication status	Published - 9 Dec 2021

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10.1021/acs.jmedchem.1c01407

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Tran, W., Kusay, A. S., Hawkins, P. M. E., Cheung, C. Y., Nagalingam, G., Pujari, V., Ford, D. J., Stoye, A., Ochoa, J. L., Audette, R. E., Hortle, E., Oehlers, S. H., Charman, S. A., Linington, R. G., Rubin, E. J., Dowson, C. G., Roper, D. I., Crick, D. C., Balle, T., ... Payne, R. J. (2021). Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase i Inhibitors. Journal of Medicinal Chemistry, 64(23), 17326-17345. https://doi.org/10.1021/acs.jmedchem.1c01407

@article{14bd365e05e14c21b46efcdfffde5e2c,

title = "Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase i Inhibitors",

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.",

author = "Wendy Tran and Kusay, {Ali S.} and Hawkins, {Paige M.E.} and Cheung, {Chen Yi} and Gayathri Nagalingam and Venugopal Pujari and Ford, {Daniel J.} and Alexander Stoye and Ochoa, {Jessica L.} and Audette, {Rebecca E.} and Elinor Hortle and Oehlers, {Stefan H.} and Charman, {Susan A.} and Linington, {Roger G.} and Rubin, {Eric J.} and Dowson, {Christopher G.} and Roper, {David I.} and Crick, {Dean C.} and Thomas Balle and Cook, {Gregory M.} and Britton, {Warwick J.} and Payne, {Richard J.}",

note = "Funding Information: The authors acknowledge the National Health and Medical Research Council of Australia (project grant APP1141142) for funding and the Australian Research and Training Scholarship for Ph.D. stipends (W.T. and P.H.). They also acknowledge Dr. Ian J. Luck (Sydney Analytical, The University of Sydney) for technical support with NMR spectroscopy, Dr. Nicholas Prochogo (The University of Sydney) for technical support with mass spectrometry, and Dr. Cody Szczepina (The University of Sydney) for technical support with HPLC. The authors thank A/Prof. Megan O{\textquoteright}Mara and Hugo MacDermott-Opeskin for advice on molecular dynamics. They also acknowledge Dr. William Jacobs (Albert Einstein College of Medicine, New York) for providing the Mtb mc 6230 strain. 2 Publisher Copyright: {\textcopyright}",

year = "2021",

month = dec,

day = "9",

doi = "10.1021/acs.jmedchem.1c01407",

language = "English",

volume = "64",

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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 2021, 'Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase i Inhibitors', Journal of Medicinal Chemistry, vol. 64, no. 23, pp. 17326-17345. https://doi.org/10.1021/acs.jmedchem.1c01407

TY - JOUR

T1 - Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase i Inhibitors

AU - Tran, Wendy

AU - Kusay, Ali S.

AU - Hawkins, Paige M.E.

AU - Cheung, Chen Yi

AU - Nagalingam, Gayathri

AU - Pujari, Venugopal

AU - Ford, Daniel J.

AU - Stoye, Alexander

AU - Ochoa, Jessica L.

AU - Audette, Rebecca E.

AU - Hortle, Elinor

AU - Oehlers, Stefan H.

AU - Charman, Susan A.

AU - Linington, Roger G.

AU - Rubin, Eric J.

AU - Dowson, Christopher G.

AU - Roper, David I.

AU - Crick, Dean C.

AU - Balle, Thomas

AU - Cook, Gregory M.

AU - Britton, Warwick J.

AU - Payne, Richard J.

N1 - Funding Information: The authors acknowledge the National Health and Medical Research Council of Australia (project grant APP1141142) for funding and the Australian Research and Training Scholarship for Ph.D. stipends (W.T. and P.H.). They also acknowledge Dr. Ian J. Luck (Sydney Analytical, The University of Sydney) for technical support with NMR spectroscopy, Dr. Nicholas Prochogo (The University of Sydney) for technical support with mass spectrometry, and Dr. Cody Szczepina (The University of Sydney) for technical support with HPLC. The authors thank A/Prof. Megan O’Mara and Hugo MacDermott-Opeskin for advice on molecular dynamics. They also acknowledge Dr. William Jacobs (Albert Einstein College of Medicine, New York) for providing the Mtb mc 6230 strain. 2 Publisher Copyright: ©

PY - 2021/12/9

Y1 - 2021/12/9

N2 - 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.

AB - 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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U2 - 10.1021/acs.jmedchem.1c01407

DO - 10.1021/acs.jmedchem.1c01407

M3 - Article

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AN - SCOPUS:85120754977

SN - 0022-2623

VL - 64

SP - 17326

EP - 17345

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 23

ER -

Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase i Inhibitors

Abstract

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Novel TB Drug Candidates via the Inhibition of Lipid I Biosynthesis

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Synthetic Sansanmycin Analogues as Potent Mycobacterium tuberculosis Translocase i Inhibitors

Abstract

UN SDGs

Access to Document

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Novel TB Drug Candidates via the Inhibition of Lipid I Biosynthesis

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