Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13

Anup Aggarwal; Maloy K. Parai; Nishant Shetty; Deeann Wallis; Lisa Woolhiser; Courtney Hastings; Noton K. Dutta; Stacy Galaviz; Ramesh C. Dhakal; Rupesh Shrestha; Shoko Wakabayashi; Chris Walpole; David Matthews; David Floyd; Paul Scullion; Jennifer Riley; Ola Epemolu; Suzanne Norval; Thomas Snavely; Gregory T. Robertson; Eric J. Rubin; Thomas R. Ioerger; Frik A. Sirgel; Ruben van der Merwe; Paul D. van Helden; Peter Keller; Erik C. Böttger; Petros C. Karakousis; Anne J. Lenaerts; James C. Sacchettini

doi:10.1016/j.cell.2017.06.025

Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13

Anup Aggarwal, Maloy K. Parai, Nishant Shetty, Deeann Wallis, Lisa Woolhiser, Courtney Hastings, Noton K. Dutta, Stacy Galaviz, Ramesh C. Dhakal, Rupesh Shrestha, Shoko Wakabayashi, Chris Walpole, David Matthews, David Floyd, Paul Scullion, Jennifer Riley, Ola Epemolu, Suzanne Norval, Thomas Snavely, Gregory T. RobertsonEric J. Rubin, Thomas R. Ioerger, Frik A. Sirgel, Ruben van der Merwe, Paul D. van Helden, Peter Keller, Erik C. Böttger, Petros C. Karakousis, Anne J. Lenaerts, James C. Sacchettini

School of Medicine

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

69 Scopus citations

Abstract

Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection.

Original language	English (US)
Pages (from-to)	249-259.e25
Journal	Cell
Volume	170
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2017.06.025
State	Published - Jul 13 2017

Keywords

Mycobacterium tuberculosis
Pks13 thioesterase domain
benzofuran inhibitors
crystal structure
polyketide synthase
structure-based drug discovery

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2017.06.025

Cite this

Aggarwal, A., Parai, M. K., Shetty, N., Wallis, D., Woolhiser, L., Hastings, C., Dutta, N. K., Galaviz, S., Dhakal, R. C., Shrestha, R., Wakabayashi, S., Walpole, C., Matthews, D., Floyd, D., Scullion, P., Riley, J., Epemolu, O., Norval, S., Snavely, T., ... Sacchettini, J. C. (2017). Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13. Cell, 170(2), 249-259.e25. https://doi.org/10.1016/j.cell.2017.06.025

Aggarwal, A, Parai, MK, Shetty, N, Wallis, D, Woolhiser, L, Hastings, C, Dutta, NK, Galaviz, S, Dhakal, RC, Shrestha, R, Wakabayashi, S, Walpole, C, Matthews, D, Floyd, D, Scullion, P, Riley, J, Epemolu, O, Norval, S, Snavely, T, Robertson, GT, Rubin, EJ, Ioerger, TR, Sirgel, FA, van der Merwe, R, van Helden, PD, Keller, P, Böttger, EC, Karakousis, PC, Lenaerts, AJ & Sacchettini, JC 2017, 'Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13', Cell, vol. 170, no. 2, pp. 249-259.e25. https://doi.org/10.1016/j.cell.2017.06.025

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abstract = "Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection.",

keywords = "Mycobacterium tuberculosis, Pks13 thioesterase domain, benzofuran inhibitors, crystal structure, polyketide synthase, structure-based drug discovery",

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AU - Shetty, Nishant

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AU - Woolhiser, Lisa

AU - Hastings, Courtney

AU - Dutta, Noton K.

AU - Galaviz, Stacy

AU - Dhakal, Ramesh C.

AU - Shrestha, Rupesh

AU - Wakabayashi, Shoko

AU - Walpole, Chris

AU - Matthews, David

AU - Floyd, David

AU - Scullion, Paul

AU - Riley, Jennifer

AU - Epemolu, Ola

AU - Norval, Suzanne

AU - Snavely, Thomas

AU - Robertson, Gregory T.

AU - Rubin, Eric J.

AU - Ioerger, Thomas R.

AU - Sirgel, Frik A.

AU - van der Merwe, Ruben

AU - van Helden, Paul D.

AU - Keller, Peter

AU - Böttger, Erik C.

AU - Karakousis, Petros C.

AU - Lenaerts, Anne J.

AU - Sacchettini, James C.

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