Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria

Energy metabolism has recently gained interest as a target space for antibiotic drug development in mycobacteria. Of particular importance is bedaquiline (Sirturo), which kills mycobacteria by inhibiting the F1F0 ATP synthase. Other components of the electron transport chain such as the NADH dehydro...

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Main Authors: Lee, Bei Shi, Kalia, Nitin Pal, Jin, Xin Er F., Hasenoehrl, Erik J., Berney, Michael, Pethe, Kevin
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2019
Subjects:
ATP
Online Access:https://hdl.handle.net/10356/103762
http://hdl.handle.net/10220/48892
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1037622020-11-01T05:19:54Z Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria Lee, Bei Shi Kalia, Nitin Pal Jin, Xin Er F. Hasenoehrl, Erik J. Berney, Michael Pethe, Kevin School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) DRNTU::Science::Medicine ATP Cell Death Energy metabolism has recently gained interest as a target space for antibiotic drug development in mycobacteria. Of particular importance is bedaquiline (Sirturo), which kills mycobacteria by inhibiting the F1F0 ATP synthase. Other components of the electron transport chain such as the NADH dehydrogenases (NDH-2 and NdhA) and the terminal respiratory oxidase bc1:aa3 are also susceptible to chemical inhibition. Because antituberculosis drugs are prescribed as part of combination therapies, the interaction between novel drugs targeting energy metabolism and classical first and second line antibiotics must be considered to maximize treatment efficiency. Here, we show that subinhibitory concentration of drugs targeting the F1F0 ATP synthase and the cytochrome bc1:aa3, as well as energy uncouplers, interfere with the bactericidal potency of isoniazid and moxifloxacin. Isoniazid- and moxifloxacin-induced mycobacterial death correlated with a transient increase in intracellular ATP that was dissipated by co-incubation with energy metabolism inhibitors. Although oxidative phosphorylation is a promising target space for drug development, a better understanding of the link between energy metabolism and antibiotic-induced mycobacterial death is essential to develop potent drug combinations for the treatment of tuberculosis. MOE (Min. of Education, S’pore) Published version 2019-06-21T01:35:30Z 2019-12-06T21:19:37Z 2019-06-21T01:35:30Z 2019-12-06T21:19:37Z 2019 Journal Article Lee, B. S., Kalia, N. P., Jin, X. E. F., Hasenoehrl, E. J., Berney, M., & Pethe, K. (2019). Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria. Journal of Biological Chemistry, 294(6), 1936-1943. doi:10.1074/jbc.RA118.005732 0021-9258 https://hdl.handle.net/10356/103762 http://hdl.handle.net/10220/48892 10.1074/jbc.RA118.005732 en Journal of Biological Chemistry © 2019 Lee et al. Published by The American Society for Biochemistry and Molecular Biology, Inc. 8 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Medicine
ATP
Cell Death
spellingShingle DRNTU::Science::Medicine
ATP
Cell Death
Lee, Bei Shi
Kalia, Nitin Pal
Jin, Xin Er F.
Hasenoehrl, Erik J.
Berney, Michael
Pethe, Kevin
Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria
description Energy metabolism has recently gained interest as a target space for antibiotic drug development in mycobacteria. Of particular importance is bedaquiline (Sirturo), which kills mycobacteria by inhibiting the F1F0 ATP synthase. Other components of the electron transport chain such as the NADH dehydrogenases (NDH-2 and NdhA) and the terminal respiratory oxidase bc1:aa3 are also susceptible to chemical inhibition. Because antituberculosis drugs are prescribed as part of combination therapies, the interaction between novel drugs targeting energy metabolism and classical first and second line antibiotics must be considered to maximize treatment efficiency. Here, we show that subinhibitory concentration of drugs targeting the F1F0 ATP synthase and the cytochrome bc1:aa3, as well as energy uncouplers, interfere with the bactericidal potency of isoniazid and moxifloxacin. Isoniazid- and moxifloxacin-induced mycobacterial death correlated with a transient increase in intracellular ATP that was dissipated by co-incubation with energy metabolism inhibitors. Although oxidative phosphorylation is a promising target space for drug development, a better understanding of the link between energy metabolism and antibiotic-induced mycobacterial death is essential to develop potent drug combinations for the treatment of tuberculosis.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Lee, Bei Shi
Kalia, Nitin Pal
Jin, Xin Er F.
Hasenoehrl, Erik J.
Berney, Michael
Pethe, Kevin
format Article
author Lee, Bei Shi
Kalia, Nitin Pal
Jin, Xin Er F.
Hasenoehrl, Erik J.
Berney, Michael
Pethe, Kevin
author_sort Lee, Bei Shi
title Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria
title_short Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria
title_full Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria
title_fullStr Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria
title_full_unstemmed Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria
title_sort inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria
publishDate 2019
url https://hdl.handle.net/10356/103762
http://hdl.handle.net/10220/48892
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