Antituberculosis Activity of the Antimalaria Cytochrome bcc Oxidase Inhibitor SCR0911.
Shi Min Sherilyn ChongMalathy Sony Subramanian ManimekalaiJickky Palmae SarathyZoe C WilliamsLiam K HaroldGregory M CookThomas DickKevin PetheRoderick W BatesGerhard GrüberPublished in: ACS infectious diseases (2020)
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.
Keyphrases
- mycobacterium tuberculosis
- structure activity relationship
- electron transfer
- single cell
- high throughput
- signaling pathway
- emergency department
- dna binding
- binding protein
- electronic health record
- transcription factor
- climate change
- case control
- bone marrow
- deep learning
- protein protein
- biofilm formation
- adverse drug
- candida albicans
- drug discovery