TY - JOUR
T1 - Antituberculosis Activity of the Antimalaria Cytochrome bcc Oxidase Inhibitor SCR0911
AU - Chong, Shi Min Sherilyn
AU - Manimekalai, Malathy Sony Subramanian
AU - Sarathy, Jickky Palmae
AU - Williams, Zoe C.
AU - Harold, Liam K.
AU - Cook, Gregory M.
AU - Dick, Thomas
AU - Pethe, Kevin
AU - Bates, Roderick W.
AU - Grüber, Gerhard
N1 - Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/4/10
Y1 - 2020/4/10
N2 - The ability to respire and generate adenosine triphosphate (ATP) is essential for the physiology, persistence, and pathogenicity of Mycobacterium tuberculosis, which causes tuberculosis. By employing a lead repurposing strategy, the malarial cytochrome bc1 inhibitor SCR0911 was tested against mycobacteria. Docking studies were carried out to reveal potential binding and to understand the binding interactions with the target, cytochrome bcc. Whole-cell-based and in vitro assays demonstrated the potency of SCR0911 by inhibiting cell growth and ATP synthesis in both the fast- and slow-growing M. smegmatis and M. bovis bacillus Calmette-Guérin, respectively. The variety of biochemical assays and the use of a cytochrome bcc deficient mutant strain validated the cytochrome bcc oxidase as the direct target of the drug. The data demonstrate the broad-spectrum activity of SCR0911 and open the door for structure-activity relationship studies to improve the potency of new mycobacteria specific SCR0911 analogues.
AB - The ability to respire and generate adenosine triphosphate (ATP) is essential for the physiology, persistence, and pathogenicity of Mycobacterium tuberculosis, which causes tuberculosis. By employing a lead repurposing strategy, the malarial cytochrome bc1 inhibitor SCR0911 was tested against mycobacteria. Docking studies were carried out to reveal potential binding and to understand the binding interactions with the target, cytochrome bcc. Whole-cell-based and in vitro assays demonstrated the potency of SCR0911 by inhibiting cell growth and ATP synthesis in both the fast- and slow-growing M. smegmatis and M. bovis bacillus Calmette-Guérin, respectively. The variety of biochemical assays and the use of a cytochrome bcc deficient mutant strain validated the cytochrome bcc oxidase as the direct target of the drug. The data demonstrate the broad-spectrum activity of SCR0911 and open the door for structure-activity relationship studies to improve the potency of new mycobacteria specific SCR0911 analogues.
KW - extremely drug resistance
KW - multidrug resistance
KW - Mycobacteria
KW - OXPHOS pathway
KW - Q203
KW - Telacebec
KW - Tuberculosis
UR - http://www.scopus.com/inward/record.url?scp=85083541791&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85083541791&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.9b00408
DO - 10.1021/acsinfecdis.9b00408
M3 - Article
C2 - 32092260
AN - SCOPUS:85083541791
SN - 2373-8227
VL - 6
SP - 725
EP - 737
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 4
ER -
