Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disease caused by Mycobacterium tuberculosis continues as a global epidemic: over 2 billion people harbor latent TB infection, and more than 9 million new TB cases, of whom 500,000 are multidrug-resistant (MDR), and nearly 2 million deaths are estimated to occur each year. New drugs are required to shorten treatment duration of drug-sensitive TB and for the treatment of MDR-TB. TMC207 is a first-in-class diarylquinoline compound with a novel mechanism of action, the inhibition of bacterial ATP synthase, and potent activity against drug-sensitive and drug-resistant TB. It has bactericidal and sterilizing activity against M. tuberculosis and other mycobacterial species, but little activity against other bacteria. In a Phase II efficacy study conducted in patients with MDR-TB taking TMC207 plus a standard background regimen, the drug appeared to be safe and well tolerated, and showed significant efficacy after 2 months of treatment with conversion rates of sputum culture of 48% (vs 9% in the placebo group). Given the product development partnership between Tibotec and the TB Alliance, the strategies of using TMC207 in shorter first-line regimens or using it in second-line regimens for drug-resistant M. tuberculosis infections are both being pursued. No clinical data of TMC207 in TB patients with HIV coinfection have been published; drug-drug interaction studies with antiretrovirals are being conducted. Finally, the remarkable sterilizing capacity of TMC207 also makes it an attractive drug in the strategy of TB elimination. Current and future studies will determine the role of TMC207 in a shortened treatment regimen for drug-sensitive TB, a more effective and better-tolerated regimen for MDR-TB, the treatment of latent TB infection, and intermittent-TB treatment regimens.
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PMID:TMC207: the first compound of a new class of potent anti-tuberculosis drugs. 2052 31

Homologous apolipoproteins of MICOS complex, MIC26 and MIC27, show an antagonistic regulation of their protein levels, making it difficult to deduce their individual functions using a single gene deletion. We obtained single and double knockout (DKO) human cells of MIC26 and MIC27 and found that DKO show more concentric onion-like cristae with loss of CJs than any single deletion indicating overlapping roles in formation of CJs. Using a combination of complexome profiling, STED nanoscopy, and blue-native gel electrophoresis, we found that MIC26 and MIC27 are dispensable for the stability and integration of the remaining MICOS subunits into the complex suggesting that they assemble late into the MICOS complex. MIC26 and MIC27 are cooperatively required for the integrity of respiratory chain (super) complexes (RCs/SC) and the F1Fo-ATP synthase complex and integration of F1 subunits into the monomeric F1Fo-ATP synthase. While cardiolipin was reduced in DKO cells, overexpression of cardiolipin synthase in DKO restores the stability of RCs/SC. Overall, we propose that MIC26 and MIC27 are cooperatively required for global integrity and stability of multimeric OXPHOS complexes by modulating cardiolipin levels.
Life Sci Alliance 2020 10
PMID:MIC26 and MIC27 cooperate to regulate cardiolipin levels and the landscape of OXPHOS complexes. 3278 26