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 - 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
U2 - 10.1016/j.chembiol.2019.10.010
DO - 10.1016/j.chembiol.2019.10.010
M3 - Article
C2 - 31711854
AN - SCOPUS:85079409128
SN - 2451-9456
VL - 27
SP - 172-185.e11
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 2
ER -