Antitubercular Triazines: Optimization and Intrabacterial Metabolism

Xin Wang; Daigo Inoyama; Riccardo Russo; Shao Gang Li; Ravindra Jadhav; Thomas P. Stratton; Nisha Mittal; Joseph A. Bilotta; Eric Singleton; Thomas Kim; Steve D. Paget; Richard S. Pottorf; Yong Mo Ahn; Alejandro Davila-Pagan; Srinivasan Kandasamy; Courtney Grady; Seema Hussain; Patricia Soteropoulos; Matthew D. Zimmerman; Hsin Pin Ho; Steven Park; Véronique Dartois; Sean Ekins; Nancy Connell; Pradeep Kumar; Joel S. Freundlich

doi:10.1016/j.chembiol.2019.10.010

Antitubercular Triazines: Optimization and Intrabacterial Metabolism

Xin Wang, Daigo Inoyama, Riccardo Russo, Shao Gang Li, Ravindra Jadhav, Thomas P. Stratton, Nisha Mittal, Joseph A. Bilotta, Eric Singleton, Thomas Kim, Steve D. Paget, Richard S. Pottorf, Yong Mo Ahn, Alejandro Davila-Pagan, Srinivasan Kandasamy, Courtney Grady, Seema Hussain, Patricia Soteropoulos, Matthew D. Zimmerman, Hsin Pin HoSteven Park, Véronique Dartois, Sean Ekins, Nancy Connell, Pradeep Kumar, Joel S. Freundlich

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

8 Scopus citations

Abstract

The triazine antitubercular JSF-2019 was of interest due to its in vitro efficacy and the nitro group shared with the clinically relevant delamanid and pretomanid. JSF-2019 undergoes activation requiring F₄₂₀H₂ and one or more nitroreductases in addition to Ddn. An intrabacterial drug metabolism (IBDM) platform was leveraged to demonstrate the system kinetics, evidencing formation of NO^⋅ and a des-nitro metabolite. Structure-activity relationship studies focused on improving the solubility and mouse pharmacokinetic profile of JSF-2019 and culminated in JSF-2513, relying on the key introduction of a morpholine. Mechanistic studies with JSF-2019, JSF-2513, and other triazines stressed the significance of achieving potent in vitro efficacy via release of intrabacterial NO^⋅ along with inhibition of InhA and, more generally, the FAS-II pathway. This study highlights the importance of probing IBDM and its potential to clarify mechanism of action, which in this case is a combination of NO^⋅ release and InhA inhibition. Wang et al. disclose the optimization of a triazine antitubercular agent and probe its mechanism of action. They demonstrate the significance of studying intrabacterial drug metabolism. Through this approach and other methods, they evidence a novel mechanism involving NO^⋅ release and inhibition of the cell wall biosynthesis enzyme InhA.

Original language	English (US)
Pages (from-to)	172-185.e11
Journal	Cell Chemical Biology
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.chembiol.2019.10.010
State	Published - Feb 20 2020
Externally published	Yes

Keywords

Bayesian models
Mycobacterium tuberculosis
intrabacterial drug metabolism
nitrofuran
triazine

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2019.10.010

Cite this

Wang, X., Inoyama, D., Russo, R., Li, S. G., Jadhav, R., Stratton, T. P., Mittal, N., Bilotta, J. A., Singleton, E., Kim, T., Paget, S. D., Pottorf, R. S., Ahn, Y. M., Davila-Pagan, A., Kandasamy, S., Grady, C., Hussain, S., Soteropoulos, P., Zimmerman, M. D., ... Freundlich, J. S. (2020). Antitubercular Triazines: Optimization and Intrabacterial Metabolism. Cell Chemical Biology, 27(2), 172-185.e11. https://doi.org/10.1016/j.chembiol.2019.10.010

Wang, X, Inoyama, D, Russo, R, Li, SG, Jadhav, R, Stratton, TP, Mittal, N, Bilotta, JA, Singleton, E, Kim, T, Paget, SD, Pottorf, RS, Ahn, YM, Davila-Pagan, A, Kandasamy, S, Grady, C, Hussain, S, Soteropoulos, P, Zimmerman, MD, Ho, HP, Park, S, Dartois, V, Ekins, S, Connell, N, Kumar, P & Freundlich, JS 2020, 'Antitubercular Triazines: Optimization and Intrabacterial Metabolism', Cell Chemical Biology, vol. 27, no. 2, pp. 172-185.e11. https://doi.org/10.1016/j.chembiol.2019.10.010

@article{26c40454cdc14938a60dd4754faeefb2,

title = "Antitubercular Triazines: Optimization and Intrabacterial Metabolism",

abstract = "The triazine antitubercular JSF-2019 was of interest due to its in vitro efficacy and the nitro group shared with the clinically relevant delamanid and pretomanid. JSF-2019 undergoes activation requiring F420H2 and one or more nitroreductases in addition to Ddn. An intrabacterial drug metabolism (IBDM) platform was leveraged to demonstrate the system kinetics, evidencing formation of NO⋅ and a des-nitro metabolite. Structure-activity relationship studies focused on improving the solubility and mouse pharmacokinetic profile of JSF-2019 and culminated in JSF-2513, relying on the key introduction of a morpholine. Mechanistic studies with JSF-2019, JSF-2513, and other triazines stressed the significance of achieving potent in vitro efficacy via release of intrabacterial NO⋅ along with inhibition of InhA and, more generally, the FAS-II pathway. This study highlights the importance of probing IBDM and its potential to clarify mechanism of action, which in this case is a combination of NO⋅ release and InhA inhibition. Wang et al. disclose the optimization of a triazine antitubercular agent and probe its mechanism of action. They demonstrate the significance of studying intrabacterial drug metabolism. Through this approach and other methods, they evidence a novel mechanism involving NO⋅ release and inhibition of the cell wall biosynthesis enzyme InhA.",

keywords = "Bayesian models, Mycobacterium tuberculosis, intrabacterial drug metabolism, nitrofuran, triazine",

author = "Xin Wang and Daigo Inoyama and Riccardo Russo and Li, {Shao Gang} and Ravindra Jadhav and Stratton, {Thomas P.} and Nisha Mittal and Bilotta, {Joseph A.} and Eric Singleton and Thomas Kim and Paget, {Steve D.} and Pottorf, {Richard S.} and Ahn, {Yong Mo} and Alejandro Davila-Pagan and Srinivasan Kandasamy and Courtney Grady and Seema Hussain and Patricia Soteropoulos and Zimmerman, {Matthew D.} and Ho, {Hsin Pin} and Steven Park and V{\'e}ronique Dartois and Sean Ekins and Nancy Connell and Pradeep Kumar and Freundlich, {Joel S.}",

note = "Funding Information: J.S.F., N.C., and V.D. acknowledge support from award number U19AI109713 NIH/ NIAID for the “Center to develop therapeutic countermeasures to high-threat bacterial agents,” from the National Institutes of Health: Centers of Excellence for Translational Research (CETR). J.S.F. and S.E. acknowledge support from award number R41AI122434 “Optimization of small molecule triazine antituberculars for in vivo efficacy” from NIH/ NIAID . Dr. John J. Piwinski is thanked for helpful discussions. We gratefully acknowledge access to the HPC facilities and support of the computational STEM and bioinformatics scientists from the Office of Advanced Research Computing (OARC) at Rutgers University. We further acknowledge the critical work made possible through access to the Perceval Linux cluster operated by OARC under NIH 1S10OD012346-01A1 and the Illumina NextSeq500 operated by the Genomics Center under NIH 1S10OD018206-01A1 . Dr. John Eng, Mr. Saw Kyin, and Mr. Henry Shwe (Princeton University) are thanked for guidance with the HRMS studies. Biovia is kindly acknowledged for providing Discovery Studio. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2020",

month = feb,

day = "20",

doi = "10.1016/j.chembiol.2019.10.010",

language = "English (US)",

volume = "27",

pages = "172--185.e11",

journal = "Cell Chemical Biology",

issn = "2451-9456",

publisher = "Elsevier Inc.",

number = "2",

}

TY - JOUR

T1 - Antitubercular Triazines

T2 - Optimization and Intrabacterial Metabolism

AU - Wang, Xin

AU - Inoyama, Daigo

AU - Russo, Riccardo

AU - Li, Shao Gang

AU - Jadhav, Ravindra

AU - Stratton, Thomas P.

AU - Mittal, Nisha

AU - Bilotta, Joseph A.

AU - Singleton, Eric

AU - Kim, Thomas

AU - Paget, Steve D.

AU - Pottorf, Richard S.

AU - Ahn, Yong Mo

AU - Davila-Pagan, Alejandro

AU - Kandasamy, Srinivasan

AU - Grady, Courtney

AU - Hussain, Seema

AU - Soteropoulos, Patricia

AU - Zimmerman, Matthew D.

AU - Ho, Hsin Pin

AU - Park, Steven

AU - Dartois, Véronique

AU - Ekins, Sean

AU - Connell, Nancy

AU - Kumar, Pradeep

AU - Freundlich, Joel S.

N1 - Funding Information: J.S.F., N.C., and V.D. acknowledge support from award number U19AI109713 NIH/ NIAID for the “Center to develop therapeutic countermeasures to high-threat bacterial agents,” from the National Institutes of Health: Centers of Excellence for Translational Research (CETR). J.S.F. and S.E. acknowledge support from award number R41AI122434 “Optimization of small molecule triazine antituberculars for in vivo efficacy” from NIH/ NIAID . Dr. John J. Piwinski is thanked for helpful discussions. We gratefully acknowledge access to the HPC facilities and support of the computational STEM and bioinformatics scientists from the Office of Advanced Research Computing (OARC) at Rutgers University. We further acknowledge the critical work made possible through access to the Perceval Linux cluster operated by OARC under NIH 1S10OD012346-01A1 and the Illumina NextSeq500 operated by the Genomics Center under NIH 1S10OD018206-01A1 . Dr. John Eng, Mr. Saw Kyin, and Mr. Henry Shwe (Princeton University) are thanked for guidance with the HRMS studies. Biovia is kindly acknowledged for providing Discovery Studio. Publisher Copyright: © 2019 Elsevier Ltd

PY - 2020/2/20

Y1 - 2020/2/20

N2 - The triazine antitubercular JSF-2019 was of interest due to its in vitro efficacy and the nitro group shared with the clinically relevant delamanid and pretomanid. JSF-2019 undergoes activation requiring F420H2 and one or more nitroreductases in addition to Ddn. An intrabacterial drug metabolism (IBDM) platform was leveraged to demonstrate the system kinetics, evidencing formation of NO⋅ and a des-nitro metabolite. Structure-activity relationship studies focused on improving the solubility and mouse pharmacokinetic profile of JSF-2019 and culminated in JSF-2513, relying on the key introduction of a morpholine. Mechanistic studies with JSF-2019, JSF-2513, and other triazines stressed the significance of achieving potent in vitro efficacy via release of intrabacterial NO⋅ along with inhibition of InhA and, more generally, the FAS-II pathway. This study highlights the importance of probing IBDM and its potential to clarify mechanism of action, which in this case is a combination of NO⋅ release and InhA inhibition. Wang et al. disclose the optimization of a triazine antitubercular agent and probe its mechanism of action. They demonstrate the significance of studying intrabacterial drug metabolism. Through this approach and other methods, they evidence a novel mechanism involving NO⋅ release and inhibition of the cell wall biosynthesis enzyme InhA.

AB - The triazine antitubercular JSF-2019 was of interest due to its in vitro efficacy and the nitro group shared with the clinically relevant delamanid and pretomanid. JSF-2019 undergoes activation requiring F420H2 and one or more nitroreductases in addition to Ddn. An intrabacterial drug metabolism (IBDM) platform was leveraged to demonstrate the system kinetics, evidencing formation of NO⋅ and a des-nitro metabolite. Structure-activity relationship studies focused on improving the solubility and mouse pharmacokinetic profile of JSF-2019 and culminated in JSF-2513, relying on the key introduction of a morpholine. Mechanistic studies with JSF-2019, JSF-2513, and other triazines stressed the significance of achieving potent in vitro efficacy via release of intrabacterial NO⋅ along with inhibition of InhA and, more generally, the FAS-II pathway. This study highlights the importance of probing IBDM and its potential to clarify mechanism of action, which in this case is a combination of NO⋅ release and InhA inhibition. Wang et al. disclose the optimization of a triazine antitubercular agent and probe its mechanism of action. They demonstrate the significance of studying intrabacterial drug metabolism. Through this approach and other methods, they evidence a novel mechanism involving NO⋅ release and inhibition of the cell wall biosynthesis enzyme InhA.

KW - Bayesian models

KW - Mycobacterium tuberculosis

KW - intrabacterial drug metabolism

KW - nitrofuran

KW - triazine

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UR - http://www.scopus.com/inward/citedby.url?scp=85079409128&partnerID=8YFLogxK

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DO - 10.1016/j.chembiol.2019.10.010

M3 - Article

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SN - 2451-9456

VL - 27

SP - 172-185.e11

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 2

ER -

Antitubercular Triazines: Optimization and Intrabacterial Metabolism

Abstract

Keywords

ASJC Scopus subject areas

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