The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule inhibition of cytochrome bd.

P. Lu, A.H.O. Asseri, Martijn Kremer, Janneke Maaskant, Roy Ummels, H. Lill, D. Bald

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Mycobacterial energy metabolism currently attracts strong attention as new target space for development of anti-tuberculosis drugs. The imidazopyridine Q203 targets the cytochrome bcc complex of the respiratory chain, a key component in energy metabolism. Q203 blocks growth of Mycobacterium tuberculosis at nanomolar concentrations, however, it fails to actually kill the bacteria, which may limit the clinical applicability of this candidate drug. In this report we show that inhibition of cytochrome bd, a parallel branch of the mycobacterial respiratory chain, by aurachin D invoked bactericidal activity of Q203. In biochemical assays using inverted membrane vesicles from Mycobacterium tuberculosis and Mycobacterium smegmatis we found that inhibition of respiratory chain activity by Q203 was incomplete, but could be enhanced by inactivation of cytochrome bd, either by genetic knock-out or by inhibition with aurachin D. These results indicate that simultaneously targeting the cytochrome bcc and the cytochrome bd branch of the mycobacterial respiratory chain may turn out as effective strategy for combating M. tuberculosis.
LanguageEnglish
JournalScientific Reports
Volume8
DOIs
Publication statusPublished - 8 Feb 2018

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Cytochromes
Electron Transport
Mycobacterium tuberculosis
Energy Metabolism
Mycobacterium smegmatis
Pharmaceutical Preparations
Tuberculosis
6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl) imidazo(1,2-a)pyridine-3-carboxamide
Bacteria
Membranes
Growth
aurachin D

Cite this

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title = "The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule inhibition of cytochrome bd.",
abstract = "Mycobacterial energy metabolism currently attracts strong attention as new target space for development of anti-tuberculosis drugs. The imidazopyridine Q203 targets the cytochrome bcc complex of the respiratory chain, a key component in energy metabolism. Q203 blocks growth of Mycobacterium tuberculosis at nanomolar concentrations, however, it fails to actually kill the bacteria, which may limit the clinical applicability of this candidate drug. In this report we show that inhibition of cytochrome bd, a parallel branch of the mycobacterial respiratory chain, by aurachin D invoked bactericidal activity of Q203. In biochemical assays using inverted membrane vesicles from Mycobacterium tuberculosis and Mycobacterium smegmatis we found that inhibition of respiratory chain activity by Q203 was incomplete, but could be enhanced by inactivation of cytochrome bd, either by genetic knock-out or by inhibition with aurachin D. These results indicate that simultaneously targeting the cytochrome bcc and the cytochrome bd branch of the mycobacterial respiratory chain may turn out as effective strategy for combating M. tuberculosis.",
author = "P. Lu and A.H.O. Asseri and Martijn Kremer and Janneke Maaskant and Roy Ummels and H. Lill and D. Bald",
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doi = "10.1038/s41598-018-20989-8",
language = "English",
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journal = "Scientific Reports",
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The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule inhibition of cytochrome bd. / Lu, P.; Asseri, A.H.O.; Kremer, Martijn; Maaskant, Janneke; Ummels, Roy; Lill, H.; Bald, D.

In: Scientific Reports, Vol. 8, 08.02.2018.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

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AU - Lu, P.

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AU - Maaskant, Janneke

AU - Ummels, Roy

AU - Lill, H.

AU - Bald, D.

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AB - Mycobacterial energy metabolism currently attracts strong attention as new target space for development of anti-tuberculosis drugs. The imidazopyridine Q203 targets the cytochrome bcc complex of the respiratory chain, a key component in energy metabolism. Q203 blocks growth of Mycobacterium tuberculosis at nanomolar concentrations, however, it fails to actually kill the bacteria, which may limit the clinical applicability of this candidate drug. In this report we show that inhibition of cytochrome bd, a parallel branch of the mycobacterial respiratory chain, by aurachin D invoked bactericidal activity of Q203. In biochemical assays using inverted membrane vesicles from Mycobacterium tuberculosis and Mycobacterium smegmatis we found that inhibition of respiratory chain activity by Q203 was incomplete, but could be enhanced by inactivation of cytochrome bd, either by genetic knock-out or by inhibition with aurachin D. These results indicate that simultaneously targeting the cytochrome bcc and the cytochrome bd branch of the mycobacterial respiratory chain may turn out as effective strategy for combating M. tuberculosis.

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