TY - JOUR
T1 - Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis
AU - Lee, Bei Shi
AU - Hards, Kiel
AU - Engelhart, Curtis A.
AU - Hasenoehrl, Erik J.
AU - Kalia, Nitin P.
AU - Mackenzie, Jared S.
AU - Sviriaeva, Ekaterina
AU - Chong, Shi Min Sherilyn
AU - Manimekalai, Malathy Sony S.
AU - Koh, Vanessa H.
AU - Chan, John
AU - Xu, Jiayong
AU - Alonso, Sylvie
AU - Miller, Marvin J.
AU - Steyn, Adrie J.C.
AU - Grüber, Gerhard
AU - Schnappinger, Dirk
AU - Berney, Michael
AU - Cook, Gregory M.
AU - Moraski, Garrett C.
AU - Pethe, Kevin
N1 - Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2021/1/11
Y1 - 2021/1/11
N2 - The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F1F0 ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa3 terminal oxidase. A functional redundancy between the cytochrome bcc:aa3 and the cytochrome bd oxidase protects M. tuberculosis from Q203-induced death, highlighting the attractiveness of the bd-type terminal oxidase for drug development. Here, we employed a facile whole-cell screen approach to identify the cytochrome bd inhibitor ND-011992. Although ND-011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotic-tolerant, non-replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment.
AB - The approval of bedaquiline has placed energy metabolism in the limelight as an attractive target space for tuberculosis antibiotic development. While bedaquiline inhibits the mycobacterial F1F0 ATP synthase, small molecules targeting other components of the oxidative phosphorylation pathway have been identified. Of particular interest is Telacebec (Q203), a phase 2 drug candidate inhibitor of the cytochrome bcc:aa3 terminal oxidase. A functional redundancy between the cytochrome bcc:aa3 and the cytochrome bd oxidase protects M. tuberculosis from Q203-induced death, highlighting the attractiveness of the bd-type terminal oxidase for drug development. Here, we employed a facile whole-cell screen approach to identify the cytochrome bd inhibitor ND-011992. Although ND-011992 is ineffective on its own, it inhibits respiration and ATP homeostasis in combination with Q203. The drug combination was bactericidal against replicating and antibiotic-tolerant, non-replicating mycobacteria, and increased efficacy relative to that of a single drug in a mouse model. These findings suggest that a cytochrome bd oxidase inhibitor will add value to a drug combination targeting oxidative phosphorylation for tuberculosis treatment.
KW - Q203
KW - antibiotic-tolerance
KW - cytochrome bcc-aa3
KW - cytochrome bd oxidase
KW - oxidative phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=85097249997&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097249997&partnerID=8YFLogxK
U2 - 10.15252/emmm.202013207
DO - 10.15252/emmm.202013207
M3 - Article
C2 - 33283973
AN - SCOPUS:85097249997
SN - 1757-4676
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 1
M1 - e13207
ER -