TBAJ-876 Retains Bedaquiline’s Activity against Subunits c and ε of Mycobacterium tuberculosis F-ATP Synthase
| Autor: | Priya Ragunathan, Christopher B. Cooper, Thomas Dick, Joon Shin, Jickky Palmae Sarathy, Anna M. Upton, Gerhard Grüber |
|---|---|
| Přispěvatelé: | School of Biological Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Protein Conformation
Protein subunit Mutant Antitubercular Agents F-ATP Synthase ε subunit F-ATP synthase 03 medical and health sciences chemistry.chemical_compound Bacterial Proteins medicine Pharmacology (medical) Binding site bedaquiline Diarylquinolines Mode of action Mechanisms of Action: Physiological Effects 030304 developmental biology Pharmacology chemistry.chemical_classification ε Subunit 0303 health sciences c subunit ATP synthase biology 030306 microbiology Chemistry TBAJ-876 Mycobacterium tuberculosis diarylquinoline Molecular biology 3. Good health Protein Subunits Proton-Translocating ATPases Infectious Diseases Enzyme Biological sciences::Molecular biology [Science] Mechanism of action Biological sciences::Biochemistry [Science] biology.protein medicine.symptom Bedaquiline |
| Zdroj: | Antimicrobial Agents and Chemotherapy |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | The antituberculosis drug bedaquiline (BDQ) inhibits Mycobacterium tuberculosis F-ATP synthase by interfering with two subunits. Drug binding to the c subunit stalls the rotation of the c ring, while binding to the ε subunit blocks coupling of c ring rotation to ATP synthesis at the catalytic α3:β3 headpiece. BDQ is used for the treatment of drug-resistant tuberculosis. The antituberculosis drug bedaquiline (BDQ) inhibits Mycobacterium tuberculosis F-ATP synthase by interfering with two subunits. Drug binding to the c subunit stalls the rotation of the c ring, while binding to the ε subunit blocks coupling of c ring rotation to ATP synthesis at the catalytic α3:β3 headpiece. BDQ is used for the treatment of drug-resistant tuberculosis. However, the drug is highly lipophilic, displays a long terminal half-life, and has a cardiotoxicity liability by causing QT interval prolongation. Recent medicinal chemistry campaigns have resulted in the discovery of 3,5-dialkoxypyridine analogues of BDQ that are less lipophilic, have higher clearance, and display lower cardiotoxic potential. TBAJ-876, which is a new developmental compound of this series, shows attractive antitubercular activity and efficacy in a murine tuberculosis model. Here, we asked whether TBAJ-876 and selected analogues of the compound retain BDQ’s mechanism of action. Biochemical assays showed that TBAJ-876 is a potent inhibitor of mycobacterial F-ATP synthase. Selection of spontaneous TBAJ-876-resistant mutants identified missense mutations at BDQ’s binding site on the c subunit, suggesting that TBAJ-876 retains BDQ’s targeting of the c ring. Susceptibility testing against a strain overexpressing the ε subunit and a strain harboring an engineered mutation in BDQ’s ε subunit binding site suggest that TBAJ-876 retains BDQ’s activity on the ε subunit. Nuclear magnetic resonance (NMR) titration studies confirmed that TBAJ-876 binds to the ε subunit at BDQ’s binding site. We show that TBAJ-876 retains BDQ’s antimycobacterial mode of action. The developmental compound inhibits the mycobacterial F-ATP synthase via a dual-subunit mechanism of interfering with the functions of both the enzyme’s c and ε subunits. |
| Databáze: | OpenAIRE |
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